USOO777684.4B2

(12) United States Patent (10) Patent No.: US 7,776,844 B2 Yu et al. (45) Date of Patent: Aug. 17, 2010

(54) N-(PHOSPHONOALKYL)-AMINO ACIDS, 7,429,575 B2 9/2008 Yu et al. DERVATIVES THEREOF AND 2005, 016491.6 A1 7/2005 Leadbetter et al. COMPOSITIONS AND METHODS OF USE OTHER PUBLICATIONS (76) Inventors: Ruey J. Yu, 655 Stump Rd., Chalfont, Struninet al., 1989, CAS. 111:233525.* PA (US)18914; Eugene J. Van Scott, 3 Shi et al., 2004, CAS;142. 231739.* Hidden La., Abington, PA (US) 19001 Li et al., 2005, CAS; 143: 158351.* Sandeman et al., 2002, CAS: 137:274431.* (*) Notice: Subject to any disclaimer, the term of this Single co's i. 164: patent is extended or adjusted under 35 Stahl e et et al., al., 1995, CAS:si. 124:563.10.* U.S.C. 154(b) by 0 days. Jezowska-Bojczuk et al., 1994, CAS: 120:28.1638.* Strumin et al., 1989, CAS: 111:194894.* (21) Appl. No.: 12/428,906 Balthazor et al., 1987, CAS: 106:50457.* The Merck Index. "An Encyclopedia of Chemicals, Drugs, and (22) Filed: Apr. 23, 2009 Biologicals.” (2001) p. 1768, (2 pgs.), 13th Edition, O'Neil et al. (Ed.), Merck & Co., Inc., Whitehouse Station, N.J. (65) Prior Publication Data Wester et al., 1991, CAS: 114:242443. US 2009/0208499 A1 Aug. 20, 2009 * cited by examiner Related U.S. Application Data Primary Examiner Rei-tsang Shiao - - - (74) Attorney, Agent, or Firm Panitch Schwarze Belisario & (62) Division of application No. 12/194203, filed on Aug. Nadel LLP 19, 2008, now Pat. No. 7,572,776, which is a division of application No. 1 1/621,287, filed on Jan. 9, 2007, (57) ABSTRACT now Pat. No. 7,429,575. The present invention relates to an N-(phosphonoalkyl)- (60) Eyal application No. 60/757,614, filed on Jan. amino acid, a related compound or a derivative thereof, the s N-(phosphonoalkyl)-amino acid, related compound or derivative thereof being in a form as a free acid, salt, partial (51) Int. Cl. salt, lactone, amide or ester, or in Stereoisomeric or non 52 it.too (2006.01) S14/114: 514/399 Stereoisomeric form, other than N-(phosphonomethyl)-gly . Fi ld fici - - - - - ificati------s ------h- - - - - s 514/114 cine or N.N-bis(phosphonomethyl)-glycine. Also included is (58) Field of Classification Search ...... s a composition including an N-(phosphonoalkyl)-amino acid, 514399; 548/335.5, 170; 558/170. 156 a related compound or a derivative thereof in a form as a free See application file for complete search history. acid, salt, partial salt, lactone, amide or ester, or in Stereoiso (56) References Cited meric or non-stereoisomeric form, and a cosmetically or pharmaceutically acceptable vehicle for topical or systemic U.S. PATENT DOCUMENTS administration to a mammalian Subject, as well as a method of 3.288,846 A 11, 1966 Irani et al. administering an effective amount of Such a composition for 3,799,758 A 3, 1974 Franz alleviating or improving a condition, disorder, symptom or 3,853,530 A 12, 1974 Franz syndrome associated with at least one of a nervous, vascular, 5,259,974 A 11/1993 Chen et al. musculoskeletal or cutaneous system. 5,414,112 A * 5/1995 Dragisich ...... 562/12 6,229,045 B1 5/2001 Ringer et al. 17 Claims, No Drawings US 7,776,844 B2 1. 2 N-(PHOSPHONOALKYL)-AMINO ACIDS, that Such compounds are useful for treating various medical DERVATIVES THEREOF AND and cosmetic conditions in animals, such as mammals, and COMPOSITIONS AND METHODS OF USE including humans.

CROSS-REFERENCE TO RELATED BRIEF SUMMARY OF THE INVENTION APPLICATIONS One aspect of the present invention relates to an N-(phosphonoalkyl)-amino acid, a related compound or a This application is a divisional application of U.S. patent derivative thereof, the N-(phosphonoalkyl)-amino acid, application Ser. No. 12/194.203, filed Aug. 19, 2008, now 10 related compound or derivative thereof being in a form as a allowed, which is a divisional application of U.S. patent free acid, salt, partial salt, lactone, amide or ester, or in Ste application Ser. No. 1 1/621,287, filed Jan. 9, 2007, now U.S. reoisomeric or non-stereoisomeric form, other than Pat. No. 7,429,575, issued Sep. 30, 2008, which claims the N-(phosphonomethyl)-glycine or N.N-bis(phosphonom benefit under 35 U.S.C.S 119(e) of U.S. Provisional Applica ethyl)-glycine. 15 Another aspect of the present invention relates to an tion No. 60/757,614, filed Jan. 10, 2006. The entire disclo N-(phosphonoalkyl)-amino acid compound, a related com sures of all of the above applications are hereby incorporated pound or a compound derived therefrom, the compound herein by reference. includes the group consisting of N-(phosphonoalkyl)-proline and a compound or derivative thereof having the following BACKGROUND OF THE INVENTION formula: The present invention relates to an N-(phosphonoalkyl)- amino acid, a related compound or a derivative thereof, the wherein R is H. an alkyl group having 1 to 19 carbon atoms, N-(phosphonoalkyl)-amino acid, related compound or an aryl group having 6 to 19 carbonatoms oran aralkyl group derivative thereof being in a form as a free acid, salt, partial 25 having 7 to 19 carbon atoms; and R can also carry —OH, salt, lactone, amide or ester, or in Stereoisomeric or non SH, -SCH, -NH = NR,R, COR - NHCONH2, Stereoisomeric form, other than N-(phosphonomethyl)-gly —NHC(=NR)NH, imidazole, pyrrolidine or other hetero cine or N,N-bis(phosphonomethyl)-glycine. The present cyclic group; m is an integer from 0 to 5; R is a phospho noalkyl group having a formula (HO)2PO(CH), ; R is H invention also relates to a composition including an 30 or a phosphonoalkyl group having a formula (HO)PO N-(phosphonoalkyl)-amino acid, a related compound or a (CH), ; n is an integer from 1 to 9; R is —NH2 or —ORs. derivative thereof in a form as a free acid, salt, partial salt, Rs is H, an alkyl group having 1 to 19 carbon atoms, an aryl lactone, amide or ester, or in Stereoisomeric or non-stereoi group having 6 to 19 carbonatoms or an aralkyl group having Someric form, and a cosmetically orpharmaceutically accept 7 to 19 carbon atoms; and the Hattached to any carbon atom able vehicle for topical or systemic administration to a mam 35 can be substituted by I, F, Cl, Br, OH or an alkoxy group malian Subject, as well as a method of administering an having 1 to 9 carbon atoms; and wherein the N-(phospho effective amount of Such a composition for alleviating or noalkyl)-amino acid, related compound or derivative thereof improving a condition, disorder, symptom or syndrome asso is in a form as a free acid, salt, partial salt, lactone, amide or ester, or in a stereoisomeric or non-stereoisomeric form; pro ciated with at least one of a nervous, vascular, musculoskel 40 vided that the compound is not N-(phosphonomethyl)-gly etal or cutaneous system. cine or N,N-bis(phosphonomethyl)-glycine. N-(Phosphonomethyl)-glycine is listed as glyphosate, Another aspect of the present invention relates to a com C.H.N.O.P. molecular weight 169, in The Merck Index, 13" position comprising an N-(phosphonoalkyl)-amino acid, a edition, 2001, page 803. The mono (isopropylamine) salt of 45 related compound or a derivative thereof, the N-(phospho N-(phosphonomethyl)-glycine is a primary active ingredient noalkyl)-amino acid, related compound or derivative thereof in Roundup(R) herbicide. N,N-Bis(phosphonomethyl)-gly being in a form as a free acid, salt, partial salt, lactone, amide cine is listed as glyphosine, CHNOP, molecular weight or ester, or in Stereoisomeric or non-stereoisomeric form, and 263, in The Merck Index, 13' edition, 2001, page 804. This a cosmetically or pharmaceutically acceptable vehicle for compound is listed as plant growth regulator known to cause 50 topical or systemic administration to a mammalian Subject. chlorosis in green plants, and also used as a chemical ripener. Yet another aspect of the present invention relates to a U.S. Pat. No. 3.288,846 entitled “Processes for Preparing method of alleviating or improving a condition, disorder, Organo-Phosphonic Acids’ describes a synthesis of N-Sub symptom or syndrome associated with at least one of a ner stituted aminomethylenephosphonic acid. U.S. Pat. No. Vous, vascular, musculoskeletal or cutaneous system, the 3,799,758 entitled “N-Phosphonomethyl-Glycine Phytotoxi 55 method comprising administering to a mammalian Subject cant Compositions' describes N-(phosphonomethyl)-glycine having the disorder, symptom or syndrome an amount effec tive for alleviating or improving the condition, disorder, and its derivatives useful as phytotoxicants and herbicides. symptom or syndrome of a composition comprising an U.S. Pat. No. 3,853,530 entitled “Regulating Plants with N-(phosphonoalkyl)-amino acid, a related compound or a N-phosphonomethyl-Glycine and Derivatives Thereof 60 derivative thereof, the N-(phosphonoalkyl)-amino acid, describes the use of N-Phosphonomethyl-glycine and deriva related compound or derivative thereof being in a form as a tives useful for regulating the natural growth and develop free acid, salt, partial salt, lactone, amide or ester, or in Ste ment of plants. reoisomeric or non-stereoisomeric form, and a cosmetically There has been no teaching, Suggestion or implication or pharmaceutically acceptable vehicle for topical or sys about the use of N-(phosphonomethyl)-glycine or its deriva 65 temic administration to the mammalian Subject. tives for topical or systemic administration to mammals, The cosmetic conditions and medical disorders, symptoms including humans. The present inventors have determined or syndromes associated with at least one of a nervous, vas US 7,776,844 B2 3 4 cular, musculoskeletal or cutaneous system, and others, nature produced by microorganisms or plants. Certain amino include, by way of example and not limitation, itch, pain, acids, such as taurine, can have a sulfonic acid group instead inflammation, erythema, eczema, dermatitis, dermatoses, of a carboxyl group. Peptides are derived from amino acids, arthritis, acne, rosacea, dry skin, ichthyosis, keratoses, pso and the peptides are called related amino acids or amino acid riasis, pigmented skin, aging related skin changes. The com derivatives. Other organic compounds which have at least one positions may also be used for skin lightening. carboxyl group and at least one alkaline group Such as amino, As used herein, the singular forms “a”, “an', and “the imino or guanidino group are also called “related amino include plural referents unless the context clearly dictates acids. As used herein, all these compounds are called related otherwise. Thus, for example, reference to “a compound amino acids. Representative, but non-limiting related amino includes a plurality of Such compounds. 10 acids include: B-alanine, Y-aminobutanoic acid, B-ami noisobutanoic acid, anserine, aminolevulinic acid, carnosine, DETAILED DESCRIPTION OF THE INVENTION canaline, canavanine, citrulline, creatine, creatinine, cysteine Sulfinic acid, cystine, cycloserine, dopa (3,4-dihydroxyphe As noted above, the present invention relates to an nylalanine), dopamine (hydroxytyramine), ethionine, glu N-(phosphonoalkyl)-amino acid, a related compound or a 15 tathione, guanidinoacetic acid, homocarnosine, homocys derivative thereof, the N-(phosphonoalkyl)-amino acid, teine, homoserine, 4-hydroxyphenylglycine, related compound or derivative thereof being in a form as a hydroxyglutamic acid, hydroxylysine, hydroxyproline, free acid, salt, partial salt, lactone, amide or ester, or in Ste hypusine, homoarginine, homocitrulline, homocystine, reoisomeric or non-stereoisomeric form, other than homophenylalanine, homotryptophan, hydroxylysine, N-(phosphonomethyl)-glycine or N.N-bis(phosphonom hydroxyarginine, hydroxyhomoarginine, hydroxycitrulline, ethyl)-glycine. hydroxyornithine, hydroxyvaline, indospicine, methoxinine, Typical, but non-limiting phosphonoalkyl groups include methylarginine, methylhistidine, methyllysine, methylorni phosphonomethyl, phosphonoethyl, phosphonopropyl. thine, methylserine, norvaline, ornithine, oxalysine, penicil phosphonoisopropyl, phosphonobutyl, phosphonoisobutyl, lamine(dimethylcysteine), phenylglycine, 3-phenylserine, phosphonopentyl, phosphonoisopentyl, phosphonooctyl and 25 sarcosine (N-methylglycine), serotonin (hydrox phosphonoisooctyl groups. ytryptamine), taurine, tryptamine and tyramine. The present invention also relates to a composition includ As used herein, the N-(phosphonoalkyl) or preferably the ing an N-(phosphonoalkyl)-amino acid, a related compound N-(phosphonomethyl) derivatives of the amino acids as or a derivative thereof in a form as a free acid, salt, partial salt, described in paragraphs 0016 and 0017 above, and certain lactone, amide or ester, or in Stereoisomeric or non-stereoi 30 others described elsewhere herein, are called “N-(phospho Someric form, and a cosmetically orpharmaceutically accept noalkyl)-related amino acids.” preferably "N-(phosphonom able vehicle for topical or systemic administration to a mam ethyl)-related amino acids.” or simply "related compounds” malian Subject. The composition includes (or other similar grammatical terms). The "derivatives N-(phosphonoalkyl)-glycine, its related compounds and thereof (or other similar grammatical forms) represent all derivatives thereof, since they are not known for use in treat 35 other compounds which are chemically derived from the ing mammals, including humans. N-(phosphonoalkyl)-amino acids, the N-(phosphonoalkyl)- The present invention additionally relates to a method of related amino acids, and preferably N-(phosphonomethyl)- administering an effective amount of Such a composition for amino acids and N-(phosphonomethyl)-related amino acids. alleviating or improving a condition, disorder, symptom or Conditions, disorders, symptoms and syndromes associ syndrome associated with at least one of a nervous, vascular, 40 ated with the (A) nervous, (B) vascular, (C) masculoskeletal, musculoskeletal or cutaneous system, or others. (D) cutaneous system, and others that may be treated with a The compositions comprising N-(phosphonoalkyl)-amino composition of the present invention can be described as acids, preferably N-(phosphonomethyl)-amino acids, related follows. compounds or derivatives thereof, and their topical or sys (A) Nervous System. temic administration to animals, such as mammals, including 45 Throughout this description, the conditions, disorders, humans, are believed to be beneficial ortherapeutically effec symptoms and syndromes associated with the nervous system tive for cosmetic conditions or medical disorders associated include the following conditions or disorders, which may with nervous, vascular, masculoskeletal, or cutaneous sys present as indicated, or otherwise: (1) dementia and Alzhe tems, or others. imer's disease: progressive loss of memory, shrinkage and The amino acid as used herein represents as a broad defi 50 atrophy of cerebral cortex, tangles of fibers in nerve cells, nition an organic compound which has at least one carboxyl senile plaques of amyloid, decreased choline acetyltrans group and at least one alkaline group Such as amino, imino or ferase enzyme; (2) carpal tunnel syndrome: weakness, pain, guanidino group. The common amino acids represent twenty tingling, numbness, burning in palm and fingers; (3) encepha amino acids which have an amino group at the alpha position litis: inflammation of the brain; (4) headache: migraine, of the carbon chain and are present in proteins. These com 55 expansion of blood vessels pressing on nerves or constriction mon amino acids are alanine, arginine, aspartic acid, aspar blocking blood Supply, inflammation, muscle contraction to agine, cysteine, glycine, glutamic acid, glutamine, histidine, face, neck or scalp; (5) meningitis: infection of spinal fluid isoleucine, leucine, lysine, methionine, phenylalanine, pro and meninges; (6) neuralgia: nerve pain, peripheral neuropa line, serine, threonine, tryptophan, tyrosine and valine. From thy, Sciatica, shingles, trigeminal neuralgia; (7) Parkinson's these common amino acids, twenty N-(phosphonoalkyl)- 60 disease: tremors in limbs, muscular rigidity; (8) amnesia: loss amino acids, preferably twenty N-(phosphonomethyl)-amino of memory and inability to form new memory; and (9) others, acids can beformed including different stereoisomers such as Such as ataxia, Bell's palsy, epilepsy, multiple Sclerosis, D., L and DL forms. myasthenia gravis, narcolepsy, paralysis and rabies. Some amino acids are metabolites or are related to or (B) Vascular System. derived from the common amino acids. Other amino acids 65 Throughout this description, Vascular conditions, reactions have amino group(s) at other positions of the carbon chain, and disorders that may be treated with a composition of the such as the Bory position. Still other amino acids are found in present invention include acanthosis nigricans, acrocyanosis, US 7,776,844 B2 5 6 actinic cheilitis, actinic prurigo, dermatitis, dermatosis, der ease (Rochalinaea hemselae), Syphilis, lyme disease (Borre mographism, dyshidrosis, drug eruptions, eczema, erythema, lia burgdorferi), cutaneous anthrax (Bacillus anthracis), erythema migrans, erythrocyanosis, erythromelalgia, famil gonococcal septicaemia, inoculation tuberculosis, scrofulo ial hemorrhage, histamine reaction, inflammatory papular derma, tuberculides, erythema induratum, leprosy (Mycobac and pustular lesions, lichen planus, lupus erythematosus, terium leprae), mycobacterium ulcerans, leishmaniasis and mycosis fungoides, neurodermatitis, neuropeptide and neu acute paronychia. The viral infections can cause viral warts rovascular reactions, parapsoriasis, perniosis (chilblains), (human papilloma virus), varicella (chickenpox), herpes photoallergy, photoreaction, photosensitivity, pityriasis Zoster (varicella-Zoster), herpes simplex (herpesvirus homi rosea, pityriasis rubra pilaris, polymorphic light eruption, nis), molluscum contagiosum, orf, AIDS (acquired immuno psoriasis, rhinophyma, rosacea, Sclerosis, spider naevi, T-cell 10 deficiency syndrome, human immunodeficiency virus, HIV). disorders, telangiectasia, urticaria and other vascular reac herpangina, mucocutaneous lymph node syndrome (Kawasa tions. ki's disease), Gianotti-Crosti syndrome (hepatitis B virus), (C) Musculoskeletal System. measles, rubella and erythema infectiosum. The fungal infec The conditions or abnormalities of musculoskeletal system tions can cause ringworm, tinea pedis (athlete's foot), tinea include the following conditions or disorders, which may 15 nails, tinea hands, tinea groin, tinea trunk and limbs, tinea present as indicated, or otherwise: (1) osteoporosis: reduction capitis (Scalp), oral candidiasis, candida intertrigo, genital of calcium in bone leading to thin bone and bone Susceptible candidiasis, chronic paronychia, chronic mucocutaneous to fracture; (2) osteoarthritis: inflammation of joint cartilage candidiasis, pityriasis versicolor, histoplasmosis, coccidio provoking Swelling and pain; (3) rheumatoid arthritis: idomycosis, blastomycosis, sporotrichosis, actinomycosis inflammation of synovium and destruction of cartilage, dam and mycetoma (madura foot). age to heart, lungs, nerves and eyes; (4) ankylosing spondyli The systemic administration includes parenteral injection, tis: arthritis affecting Sacroiliac joints and spine with inflam Such as intravenous or intraarterial injection or infusion, Sub mation and immovability; (5) bursitis: inflammation of bursa; cutaneous, intramuscular or other injection, as well as oral, (6) tendinitis: inflammation of tendon; (7) gout: recurrent transdermal and other routes. The preferred systemic admin acute arthritis from uric acid deposit; and (8) others, such as 25 istration is oral administration. backache, bunion and hernia. Certain N-(phosphonoalkyl)-amino acids, related com (D) Cutaneous System, and Others. pounds and derivatives thereof can be represented by the The cosmetic, dermatological or other conditions and dis following generic formula: orders of cutaneous system that my be treated with a compo sition of the present invention include deranged or disordered 30 cutaneous or mucocutaneous tissue relevant to skin, nail and hair; oral, vaginal and anal mucosa; disturbed keratinization; wherein R is H, an alkyl group having 1 to 19 carbonatoms, inflammation; changes associated with intrinsic and extrinsic an aryl group having 6 to 19 carbonatoms oran aralkyl group aging, and others which may or may not be related to cuta having 7 to 19 carbon atoms; and R can also carry —OH, neous system. The manifestations include acne; rosacea; age 35 SH, -SCH, -NH = NR,R, COR - NHCONH2, spots; blemished skin; blotches; cellulite; dermatoses; der —NHC(=NR)NH, imidazole, pyrrolidine or other hetero matitis; skin, nail and hair infections; dandruff dryness or cyclic group; m is an integer from 0 to 5; R is a phospho looseness of skin, nail and hair, Xerosis: eczema: elastosis: noalkyl group having a formula (HO)2PO(CH), ; R is H herpes; hyperkeratosis; hyperpigmented skin; ichthyosis: or a phosphonoalkyl group having a formula (HO)PO keratoses; lentigines; melasmas; mottled skin; pseudofollicu 40 (CH2)—; n is an integer from 1 to 9; R is —NH2 or —ORs, litis barbae; photoaging and photodamage; pruritus; psoria Rs is H, an alkyl group having 1 to 19 carbon atoms, an aryl sis; skin lines; stretch marks; thinning of skin, nail plate and group having 6 to 19 carbonatoms or an aralkyl group having hair, warts; wrinkles; oral or gum disease; irritated, inflamed, 7 to 19 carbon atoms; and the Hattached to any carbon atom red, unhealthy, damaged or abnormal mucosa, skin, hair, nail, can be substituted by I, F, Cl, Br, OH or an alkoxy group nostril, ear canal, anal or vaginal conditions; breakdown, 45 having 1 to 9 carbon atoms. Typical, but non-limiting defective synthesis or repair of dermal components; abnormal phosphonoalkyl groups include phosphonomethyl, phospho or diminished synthesis of collagen, glycosaminoglycans, noethyl, phosphonopropyl, phosphonoisopropyl, phospho proteoglycans and elastin, as well as diminished levels of nobutyl, phosphonoisobutyl, phosphonopentyl, phospho Such components in the dermis; uneven skintone; uneven and noisopentyl, phosphonooctyl and phosphonoisooctyl groups. rough surface of skin, nail and hair, loss or reduction of skin, 50 The most preferred one is phosphonomethyl group. The nail and hair resiliency, elasticity and recoilability: laxity: N-(phosphonoalkyl)-amino acid, related compound or lack of skin, nail and hair lubricants and luster, fragility and derivative thereof can be present in a form as free acid, salt or splitting of nail and hair, yellowing skin; reactive, irritating or partial salt with organic or inorganic alkali, amide, ester or telangiectatic skin; and dull and older-looking skin, nail and lactone, as a stereoisomer Such as in D. L., or DL form, or as hair. In addition, N-(phosphonoalkyl)-amino acids can be 55 a non-stereoisomer Such as N-(phosphonoalkyl)-3-alanine. used for general care of skin, nail and hair; to improve skin Among N-(phosphonoalkyl)-amino acids, N-(phospho texture and pores, flakiness and redness; to make skin Soft, noalkyl)-proline cannot be represented by the above generic Smooth, fresh, balanced, visibly clear, even-toned and structure because the C-amino group is part of the heterocy brighter; to increase skin fullness and plumpness; and for skin clic pyrrolidine ring. Therefore, N-(phosphonoalkyl) deriva bleach and lightening and wound healing. 60 tives of proline Such as N-(phosphonoalkyl)-proline, Skin, nail and hair infections can be caused by microor N-(phosphonoalkyl)-prolinamide and N-(phosphonoalkyl)- ganisms which include bacteria, fungi, yeasts, molds, para proline esters will be represented by their chemical names. In sites and viruses. More specifically, the bacterial infections the same manner, chemical names will be used if other com can cause trichomycosis axillaris, pitted keratolysis, erythr pounds of the present invention cannot be covered by the asma, impetigo, eethyma, furunculosis (boils), carbuncle, 65 above generic structure. Scalded skin syndrome, toxic shock syndrome, erysipelas, Each of the amino groups of an amino acid excluding cellulitis, necrotizing fasciitis, erysipeloid, cat-scratch dis proline has two hydrogen atoms attached to the nitrogen

US 7,776,844 B2 9 10 N,N-bis(phosphonoalkyl)-hypusine; N,N-bis(phospho As aforementioned, each of any of the amino groups of an noalkyl)-homoarginine; N.N-bis(phosphonoalkyl)-homoc amino acid excluding proline has two hydrogen atoms itrulline; N.N-bis(phosphonoalkyl)-homocystine; N.N-bis attached to the nitrogen atom, and can form bis- or di (phosphonoalkyl)-homophenylalanine; N,N-bis (phosphonomethyl)-amino acid such as N,N-bis(phospho (phosphonoalkyl)-homotryptophan; N,N-bis nomethyl)-cysteine and N,N-bis(phosphonomethyl)-leucine. (phosphonoalkyl)-hydroxylysine; N,N-bis Most amino acids and related amino acids have only one (phosphonoalkyl)-hydroxyarginine; N,N-bis amino group attached to the alpha or other position of the (phosphonoalkyl)-hydroxyhomoarginine; N,N-bis carbon atom, and can have only one or two (phosphonom (phosphonoalkyl)-hydroxycitrulline; N,N-bis ethyl) groups attached to the amino group Such as (phosphonoalkyl)-hydroxyomithine; N,N-bis 10 N-(phosphonomethyl)-serine and N,N-bis(phosphonom (phosphonoalkyl)-hydroxyvaline; N,N-bis ethyl)-serine. Some amino acids and related amino acids, (phosphonoalkyl)-indospicine; N.N-bis(phosphonoalkyl)- Such as lysine, ornithine, arginine, histidine and tryptophan methoxinine; N,N-bis(phosphonoalkyl)-methylarginine: have additional amino, imino or guanidino group in addition N,N-bis(phosphonoalkyl)-methylhistidine; N,N-bis to the alpha amino group, and can form one to four (phospho (phosphonoalkyl)-methyllysine; N.N-bis(phosphonoalkyl)- 15 nomethyl) groups, such as N-(phosphonomethyl)-amino methylomithine; N.N-bis(phosphonoalkyl)-methylserine; acids: N'-(phosphonomethyl)-amino acids; N,N-bis N,N-bis(phosphonoalkyl)-norvaline; N,N-bis(phospho (phosphonomethyl)-amino acids; N,N'-bis(phosphonom noalkyl)-ornithine; N,N-bis(phosphonoalkyl)-oxalysine; ethyl)-amino acids; N'N'-bis(phosphonomethyl)-amino N,N-bis(phosphonoalkyl)-penicillamine (N-phospho acids: N.N.N'-tris(phosphonomethyl)-amino acids: N,N',N'- noalkyl-dimethylcysteine); N,N-bis(phosphonoalkyl)-phe tris(phosphonomethyl)-amino acids and N.N.N'N'-tetra nylglycine; N,N-bis(phosphonoalkyl)-3-phenylserine; N.N- (phosphonomethyl)-amino acids. Non-limiting examples are bis(phosphonoalkyl)-serotonin (N-phosphonoalkyl N-(phosphonomethyl)-lysine; N'-(phosphonomethyl)- hydroxytryptamine); N,N-bis(phosphonoalkyl)-taurine; lysine; N,N-bis(phosphonomethyl)-lysine; N,N'-bis N,N-bis(phosphonoalkyl)-tryptamine and N,N-bis(phospho (phosphonomethyl)-lysine; N',N'-bis(phosphonomethyl)- noalkyl)-tyramine. These di- or bis-substituted related amino 25 lysine; N.N.N'-tris(phosphonomethyl)-lysine; N.N'N'-tris acids are included with the invention as derivatives of related (phosphonomethyl)-lysine and N,N,N',N'-tetra amino acids. (phosphonomethyl)-lysine. A presently more preferred Any of the above phosphonoalkyl-amino acids, related N-(phosphonomethyl) derivative is a single phosphonom compounds and derivatives thereof can be present as a free ethyl radical attached to an amino group of an amino acid or acid, salt or partial salt with organic or inorganic alkali, lac 30 related amino acid, Such as alpha N-(phosphonomethyl)- tone, amide, ester or in Stereoisomeric or non-stereoisomeric lysine and N-(phosphonomethyl)-y-aminobutanoic acid. form. The preferred mono-substituted common amino acids As an illustration, N-(phosphonoalkyl)-proline includes include: for example, N-(phosphonoalkyl)-L-proline, N-(phospho N-(phosphonomethyl)-alanine, N-(phosphonomethyl)- noalkyl)-L-proline Sodium salt, N-(phosphonoalkyl)-L-pro 35 arginine, N-(phosphonomethyl)-asparagine, N-(phospho linamide, N-(phosphonoalkyl)-L-proline methyl ester, nomethyl)-aspartic acid, N-(phosphonomethyl)-cysteine, N-(phosphonoalkyl)-L-proline ethyl ester, N-(phospho N-(phosphonomethyl)-glycine, N-(phosphonomethyl)- noalkyl)-L-proline propyl ester and N-(phosphonoalkyl)-L- glutamic acid, N-(phosphonomethyl)-glutamine, proline isopropyl ester. N-(phosphonomethyl)-histidine, N-(phosphonomethyl)-iso The preferred phosphonoalkyl groups are phosphonom 40 leucine, N-(phosphonomethyl)-leucine, N-(phosphonom ethyl, phosphonoethyl, phosphonopropyl, phosphonoisopro ethyl)-lysine, N-(phosphonomethyl)-methionine, pyl, phosphonobutyl, phosphonoisobutyl, phosphonopentyl, N-(phosphonomethyl)-phenylalanine, N-(phosphonom phosphonoisopentyl, phosphonooctyl and phosphonoisooc ethyl)-proline, N-(phosphonomethyl)-serine, N-(phospho tyl groups. Therefore, the preferred compounds of the present nomethyl)-threonine, N-(phosphonomethyl)-tryptophan, invention are N-(phosphonomethyl)-amino acids, 45 N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)- N-(phosphonoethyl)-amino acids, N-(phosphonopropyl)- valine. These are within the category of N-(phosphonom amino acids, N-(phosphonoisopropyl)-amino acids, ethyl)-amino acids. N-(phosphonobutyl)-amino acids, N-(phosphonoisobutyl)- The preferred mono-substituted related amino acids amino acids, N-(phosphonopentyl)-amino acids, include: N-(phosphonoisopentyl)-amino acids, N-(phosphonooctyl)- 50 N-(phosphonomethyl)-3-alanine, N-(phosphonomethyl)- amino acids, N-(phosphonoisooctyl)-amino acids, and the y-aminobutanoic acid, N-(phosphonomethyl)-3-aminoisobu related amino acid compounds and derivatives thereof. The tanoic acid, N-(phosphonomethyl)-anserine, N-(phospho most preferred compounds are N-(phosphonomethyl)-amino nomethyl)-aminolevulinic acid, N-(phosphonomethyl)- acids, related compounds and derivatives thereof, in which R carnosine, N-(phosphonomethyl)-canaline, is a (phosphonomethyl) group having the formula (HO)PO 55 N-(phosphonomethyl)-canavanine, N-(phosphonomethyl)- (CH), and R is H or a phosphonomethyl group having the citrulline, N-(phosphonomethyl)-creatine, N-(phosphonom formula (HO)PO(CH) in the above generic structure. ethyl)-creatinine, N-(phosphonomethyl)-cysteine Sulfinic Among N-(phosphonomethyl)-amino acids, N-(phospho acid, N-(phosphonomethyl)-cystine, N-(phosphonomethyl)- nomethyl)-proline cannot be represented by the above cycloserine, N-(phosphonomethyl)-dopa N-(phosphonom generic structure because the alpha amino group is part of the 60 ethyl)-3,4-dihydroxyphenylalanine, N-(phosphonomethyl)- heterocyclic pyrrolidine ring. Therefore, N-(phosphonom dopamine(hydroxytyramine), N-(phosphonomethyl)- ethyl) derivatives of proline such as N-(phosphonomethyl)- ethionine, N-(phosphonomethyl)-glutathione, proline, N-(phosphonomethyl)-prolinamide and N-(phosphonomethyl)-guanidinoacetic acid, N-(phospho N-(phosphonomethyl)-proline esters will be represented by nomethyl)-3-guanidinopropanoic acid, N-(phosphonom their chemical names. In the same manner, chemical names 65 ethyl)-4-guanidinobutanoic acid, N-(phosphonomethyl)-ho will be used if other compounds of the present invention mocamosine, N-(phosphonomethyl)-homocysteine, cannot be covered by the above generic structure. N-(phosphonomethyl)-homoserine, N-(phosphonomethyl)- US 7,776,844 B2 11 12 4-hydroxyphenylglycine, N-(phosphonomethyl)-hydroxy guanidinobutanoic acid; N,N-bis(phosphonomethyl)- glutamic acid, N-(phosphonomethyl)-hydroxylysine, homocarnosine; N.N-bis(phosphonomethyl)-homocysteine; N-(phosphonomethyl)-hydroxyproline, N-(phosphonom N,N-bis(phosphonomethyl)-homoserine; N.N-bis(phospho ethyl)-hypusine, N-(phosphonomethyl)-homoarginine, nomethyl)-4-hydroxyphenylglycine; N.N-bis(phosphonom N-(phosphonomethyl)-homocitrulline, N-(phosphonom ethyl)-hydroxyglutamic acid: N,N-bis(phosphonomethyl)- ethyl)-homocystine, N-(phosphonomethyl)-homophenylala hydroxylysine; N,N-bis(phosphonomethyl)-hydroxyproline; nine, N-(phosphonomethyl)-homotryptophan, N-(phospho N,N-bis(phosphonomethyl)-hypusine; N.N-bis(phospho nomethyl)-hydroxylysine, N-(phosphonomethyl)- nomethyl)-homoarginine; N.N-bis(phosphonomethyl)-ho hydroxyarginine, N-(phosphonomethyl)- mocitrulline; N,N-bis(phosphonomethyl)-homocystine; hydroxyhomoarginine, N-(phosphonomethyl)- 10 N,N-bis(phosphonomethyl)-homophenylalanine; N.N-bis hydroxycitrulline, N-(phosphonomethyl)-hydroxyornithine, (phosphonomethyl)-homotryptophan; N,N-bis(phospho N-(phosphonomethyl)-hydroxyvaline, N-(phosphonom nomethyl)-hydroxylysine; N.N-bis(phosphonomethyl)-hy ethyl)iminodiacetic acid, N-(phosphonomethyl)-indospi droxyarginine; N,N-bis(phosphonomethyl)- cine, N-(phosphonomethyl)-methoxinine, N-(phosphonom hydroxyhomoarginine; N,N-bis(phosphonomethyl)- ethyl)-methylarginine, N-(phosphonomethyl)- 15 hydroxycitrulline: N,N-bis(phosphonomethyl)- methylhistidine, N-(phosphonomethyl)-methyllysine, hydroxyomithine; N,N-bis(phosphonomethyl)- N-(phosphonomethyl)-methylomithine, N-(phosphonom hydroxyvaline; N.N-bis(phosphonomethyl)-indospicine; ethyl)-methylserine, N-(phosphonomethyl)-norvaline, N,N-bis(phosphonomethyl)-methoxinine: N,N-bis N-(phosphonomethyl)-ornithine, N-(phosphonomethyl)-ox (phosphonomethyl)-methylarginine; N.N-bis(phosphonom alysine, N-(phosphonomethyl)-penicillamine(N-phospho ethyl)-methylhistidine; N.N-bis(phosphonomethyl)-meth nomethyl-dimethylcysteine), N-(phosphonomethyl)-phe yllysine; N.N-bis(phosphonomethyl)-methylornithine; N.N- nylglycine, N-(phosphonomethyl)-3-phenylserine, bis(phosphonomethyl)-methylserine; N,N-bis N-(phosphonomethyl)-sarcosine (N-phosphonomethyl-N- (phosphonomethyl)-norvaline; N.N-bis(phosphonomethyl)- methyl-glycine), N-(phosphonomethyl)-serotonin ornithine; N.N-bis(phosphonomethyl)-oxalysine; N.N-bis (N-phosphonomethyl-hydroxytryptamine), N-(phospho 25 (phosphonomethyl)-penicillamine(N-phosphonomethyl nomethyl)-taurine, N-(phosphonomethyl)-tryptamine and dimethylcysteine); N,N-bis(phosphonomethyl)- N-(phosphonomethyl)-tyramine. These compounds are phenylglycine; N.N-bis(phosphonomethyl)-3-phenylserine; within the category of N-(phosphonomethyl)-related amino N,N-bis(phosphonomethyl)-sarcosine (N-phosphonom acids, or simply, related compounds. ethyl-N-methyl-glycine); N,N-bis(phosphonomethyl)-sero The preferred di- or bis-substituted common amino acids 30 tonin (N-phosphonomethyl-hydroxytryptamine); N,N-bis a. (phosphonomethyl)-taurine; N.N-bis(phosphonomethyl)- N.N-bis(phosphonomethyl)-alanine; N.N-bis(phospho tryptamine; N.N-bis(phosphonomethyl)-tyramine and N,N'- nomethyl)-arginine; N.N-bis(phosphonomethyl)-aspartic bis(phosphonomethyl)-ornithine. These compounds are acid: N,N-bis(phosphonomethyl)-asparagines; N,N-bis within the category of derivatives. (phosphonomethyl)-cysteine; N.N-bis(phosphonomethyl)- 35 Any of the above phosphonomethyl-amino acids, related glycine; N.N-bis(phosphonomethyl)-glutamic acid: N,N-bis compounds and derivatives thereof can be present as a free (phosphonomethyl)-glutamine; N.N-bis(phosphonomethyl)- acid, salt, or partial salt with organic or inorganic alkali, histidine; N.N-bis(phosphonomethyl)-isoleucine; N.N-bis lactone, amide, ester or in Stereoisomeric or non-stereoiso (phosphonomethyl)-leucine; N.N-bis(phosphonomethyl)- meric form. lysine; N.N-bis(phosphonomethyl)-methionine; N.N-bis 40 As an illustration, N-(phosphonomethyl)-proline includes (phosphonomethyl)-phenylalanine; N,N-bis for example, N-(phosphonomethyl)-L-proline; N-(phospho (phosphonomethyl)-serine; N,N-bis(phosphonomethyl)- nomethyl)-L-proline sodium salt; N-(phosphonomethyl)-L- threonine; N.N-bis(phosphonomethyl)-tryptophan; N,N-bis prolinamide, N-(phosphonomethyl)-L-proline methyl ester, (phosphonomethyl)-tyrosine; N.N-bis(phosphonomethyl)- N-(phosphonomethyl)-L-proline ethyl ester, N-(phospho valine; N.N'-bis(phosphonomethyl)-arginine; N.N'-bis 45 nomethyl)-L-proline propyl ester and N-(phosphonomethyl)- (phosphonomethyl)-histidine; N.N'-bis(phosphonomethyl)- L-proline isopropyl ester. lysine and N,N'-bis(phosphonomethyl)-tryptophan. These Synthesis of N-(Phosphonomethyl)-Amino Acids and compounds are within the category of derivatives. Related Compounds The preferred di- or bis-substituted related amino acids and Among different syntheses, the most convenient and sim derivatives include: 50 plest method is the following process which is modified from N,N-bis(phosphonomethyl)-3-alanine; N.N-bis(phospho the examples described in U.S. Pat. No. 3,799,758, the dis nomethyl)-y-aminobutanoic acid, N.N-bis(phosphonom closure of which is hereby incorporated by reference herein. ethyl)-f-aminoisobutanoic acid; N,N-bis(phosphonom In general, most N-(phosphonomethyl)-amino acids and ethyl)-anserine; N.N-bis(phosphonomethyl)-aminolevulinic related compounds can be synthesized by the following acid: N,N-bis(phosphonomethyl)-carnosine; N.N-bis 55 exemplary, non-limiting method. (phosphonomethyl)-canaline; N.N-bis(phosphonomethyl)- An amino acid (1.1 mole) and chloromethyl phosphonic canavanine: N,N-bis(phosphonomethyl)-citrulline; N.N-bis acid (1 mole) in 300 ml of 8N NaOH were heated at 100° C. (phosphonomethyl)-creatine; N.N-bis(phosphonomethyl)- for 24 hours. After the reaction mixture was cooled to room creatinine; N.N-bis(phosphonomethyl)-cysteine sulfinic temperature, 250 ml of 12N HCl was slowly added with acid: N,N-bis(phosphonomethyl)-cystine; N.N-bis(phospho 60 stirring while the container was cooled externally with a nomethyl)-cycloserine; N.N-bis(phosphonomethyl)-dopaC3; cold-water bath. The mixture was filtered, and the filtrate was N,N-bis(phosphonomethyl)-4-dihydroxyphenylalanine); cooled with an ice-water bath. From the filtrate, N-(phospho N,N-bis(phosphonomethyl)-dopamine(hydroxytyramine); nomethyl)-amino acid was obtained as a precipitate which N,N-bis(phosphonomethyl)-ethionine; N.N-bis(phospho was washed with cold dilute HCl and cold water. The product nomethyl)-glutathione; N.N-bis(phosphonomethyl)-guani 65 thus obtained was identified by routine chemical methods. dinoacetic acid; N,N-bis(phosphonomethyl)-3-guanidino The ester form of an N-(phosphonomethyl)-amino acid propanoic acid; N,N-bis(phosphonomethyl)-4- was synthesized by a conventional process which included US 7,776,844 B2 13 14 heating the N-(phosphonomethyl)-amino acid in anhydrous ingredient or component with respect to the overall compo alcohol containing HCl gas. Methyl, ethyl, propyl and iso sition, unless otherwise indicated. propyl esters of an N-(phosphonomethyl)-amino acid were For example, human Subjects having severe dry skin or readily synthesized by the above simple process. For ichthyosis, topically applied 1%-5% N-(phosphonomethyl)- example, N-(phosphonomethyl)-L-proline ethyl ester, glycine creams to lesions for 2 to 3 weeks. After 2 to 3 weeks N-(phosphonomethyl)-L-tyrosine ethyl ester, N-(phospho of topical application, the thick and scaly skin disappeared nomethyl)-D-4-hydroxyphenylglycine ethyl ester, and the skin became Smooth and normal in appearance. Clini N-(phosphonomethyl)-glycine propyl ester and N-(phospho cal evaluation was judged to be 90% to 100% improvement nomethyl)-glycine isopropyl ester were synthesized from compared to the untreated condition or when using a vehicle their correspondent N-(phosphonomethyl)-amino acids by 10 control. the above process. For systemic administration, a composition comprising an The amide form of an N-(phosphonomethyl)-amino acid N-(phosphonoalkyl)-amino acid, a related compound or was also synthesized by a conventional process which derivative of the present invention, preferably an included reaction of an N-(phosphonomethyl)-amino acid N-(phosphonomethyl)-amino acid of the present invention, methyl ester with ammonia gas in anhydrous methanol. For 15 can be administered by injection, infusion or oral intake, or example, N-(phosphonomethyl)-glycinamide was synthe otherwise, with the preferred route being oral administration. sized from N-(phosphonomethyl)-glycine methyl ester by the A composition comprising an N-(phosphonoalkyl)-amino above process. acid, a related compound or derivative of the present inven The N-(phosphonoalkyl)-amino acids and related com tion, preferably an N-(phosphonomethyl)-amino acid, a pounds can be synthesized by the same procedure except that related compound or derivative can be taken orally one to chloromethyl phosphonic acid is replaced by chloroalkyl three times, and preferably twice, daily for prevention or phosphonic acid. treatment of disorders and diseases associated with nervous, By using the above process the following specific vascular, musculoskeletal or cutaneous system, or others. The N-(phosphonomethyl)-amino acids and related compounds 25 oral administration can continue until the symptom, cosmetic have been synthesized: condition, medical disorder or disease has been eradicated or N-(phosphonomethyl)-asparagine, N-(phosphonom Substantially improved. The symptoms or disorders include, ethyl)-cysteine, N-(phosphonomethyl)-glycine, N-(phospho without limitation, pains, pruritus, inflammation, erythema, nomethyl)-glutamic acid, N-(phosphonomethyl)-glutamine, dermatitis, acne, eczema, dementia, Alzheimer's disease, N-(phosphonomethyl)-proline, N-(phosphonomethyl)- joint pain or Swelling, and arthritis. Oral dosages can be about serine, N-(phosphonomethyl)-tyrosine, N-(phosphonom 30 50 mg to about 500 mg daily, preferably divided into equal ethyl)-y-aminobutanoic acid, N-(phosphonomethyl)-creat dosages of about 25 mg to about 250 mg taken twice daily. ine, N-(phosphonomethyl)-creatinine, The particularly preferred N-(phosphonomethyl)-amino N-(phosphonomethyl)-glutathione, N-(phosphonomethyl)- acids useful in the embodiments described herein, and that 4-hydroxyphenylglycine, N-(phosphonomethyl)-ornithine, 35 can be administered topically or systemically include and N-(phosphonomethyl)-tyramine. N-(phosphonomethyl)-asparagine, N-(phosphonomethyl)- A composition comprising an N-(phosphonoalkyl)-amino asparaginamide, N-(phosphonomethyl)-glycine, acid, a related compound or derivative of the present inven N-(phosphonomethyl)-glycinamide, N-(phosphonomethyl)- tion, preferably an N-(phosphonomethyl)-amino acid, a glycine ethyl ester, N-(phosphonomethyl)-glycine propyl related compound or derivative thereof is believed to be cos 40 ester, N-(phosphonomethyl)-glycine isopropyl ester, metically or therapeutically beneficial or effective and can be N-(phosphonomethyl)-proline, N-(phosphonomethyl)-proli administered topically or systemically to a mammal, includ namide, N-(phosphonomethyl)-proline ethyl ester, ing a human, Subject in need of prevention or treatment of N-(phosphonomethyl)-proline propyl ester, N-(phospho cosmetic conditions, dermatological disorders, or diseases nomethyl)-proline isopropyl ester, N-(phosphonomethyl)- associated with the nervous, vascular, musculoskeletal or 45 glutamic acid, N-(phosphonomethyl)-glutamic acid diethyl cutaneous system, or others. ester, N-(phosphonomethyl)-glutamine, N-(phosphonom For topical administration, a composition comprising an ethyl)-glutaminamide, N-(phosphonomethyl)-glutamine N-(phosphonoalkyl)-amino acid, a related compound or ethyl ester, N-(phosphonomethyl)-arginine, N-(phospho derivative of the present invention, preferably an nomethyl)-argininamide, N-(phosphonomethyl)-arginine N-(phosphonomethyl)-amino acid a related compound or 50 ethyl ester, N-(phosphonomethyl)-lysine, N-(phosphonom derivative of the present invention, can be topically applied ethyl)-lysinamide, N-(phosphonomethyl)-lysine ethyl ester, one to three times, and preferably twice, daily to the lesions or N-(phosphonomethyl)-creatine and N-(phosphonomethyl)- the cutaneous sites associated with cosmetic conditions or creatinine. medical disorders or diseases. The topical application can In accordance with preferred embodiments of the inven continue until the symptom, cosmetic condition, medical dis 55 tion, a composition is provided comprising at least one com order or disease has been eradicated or substantially pound selected from the group consisting of an N-(phospho improved. The treatment period depends on the condition or noalkyl)-amino acid, a related compound or derivative of the severity of the disorder or disease, and also depends on the present invention, preferably an N-(phosphonomethyl)- individual Subject. Examples of conditions, disorders and amino acid or derivative thereof, as free acid, ester, amide, diseases associated with nervous, vascular, musculoskeletal 60 lactone or salt form (which includes partial salts) present in a or cutaneous system, or others include, without limitation therapeutically or cosmetically effective amount and in a pains, pruritus, inflammation, erythema, dermatitis, acne, pharmaceutically or cosmetically acceptable vehicle for topi rosacea, eczema, severe dry skin, ichthyosis, age spots, pso cal or systemic treatment of disorders associated with ner riasis, wrinkles, photoaging skin, pigmented skin, and dark Vous, vascular, musculoskeletal or cutaneous system. In one skin to be lightened. 65 embodiment of the invention, the composition further com As used herein, “percent” or “96’ concerning an amount of prises a cosmetic, pharmaceutical or other topically active an ingredient or component means weight percent of the agent for synergetic or synergistic effects. US 7,776,844 B2 15 16 These cosmetic, pharmaceutical or other topically active ensis, camphor, candesartan cilexetil, capecitabine, capreo agent includes any one or more of an agent selected from mycin, capsaicin, captopril, carbamazepine, carbamide hydroxyacids, ketoacids and related compounds; phenyl peroxide, carbidopa, carbinoxamine, cefditoren pivoxil, alpha acyloxyalkanoic acids and derivatives; N-acyl-al cefepime, cefpodoxime proxetil, celecoxib, cetirizine, dosamines, N-acylamino acids and related N-acyl com cevimeline, chitosan, chlordiazepoxide, chlorhexidine, chlo pounds; local analgesics and anesthetics; anti-acne agents; roquine, chlorothiazide, chloroxylenol, chlorpheniramine, anti-bacterial agents; anti-yeast agents; anti-fungal agents; chlorpromazine, chlorpropamide, ciclopiroX, cilostaZol. anti-viral agents; anti-infective agents; anti-dandruff agents; cimetidine, cinacalcet, ciprofloxacin, citalopram, citric acid, anti-dermatitis agents; anti-eczema agents; anti-histamine cladribine, clarithromycin, clemastine, clindamycin, clio agents; anti-pruritic agents; anti-emetics; anti-motion sick 10 quinol, clobetasol propionate, clocortolone pivalate, clomi ness agents; anti-inflammatory agents; anti-hyperkeratotic phene, clonidine, clopidogrel, clotrimazole, clozapine, coal agents; antiperspirants; anti-psoriatic agents; anti-rosacea tar, coal tar extracts (LCD), codeine, cromolyn, crotamiton, agents; anti-seborrheic agents; hair conditioners and hair cyclizine, cyclobenzaprine, cycloserine, cytarabine, dacarba treatment agents; anti-aging and anti-wrinkle agents; anti Zine, dalfopristin, dapsone, daptomycin, daunorubicin, def anxiety agents; anti-convulsant agents; anti-depressant 15 eroxamine, dehydroepiandrosterone, delavirdine, agents; Sunblock and Sunscreen agents; skin lightening desipramine, desloratadine, desmopressin, desoximetaSone, agents; depigmenting agents; astringents; cleansing agents: dexamethasone, dexmedetomidine, dexmethylphenidate, corn, callus or wart removing agents; skin plumping agents; dexraZoxane, dextroamphetamine, diazepam, diclofenac, skin Volumizing agents; skin firming agents; matrix metallo dicyclomine, didanosine, dihydrocodeine, dihydromorphine, proteinase (MMP) inhibitors; topical cardiovascular agents: diltiazem, 6,8-dimercaptooctanoic acid (dihydrolipoic acid), wound-healing agents; gum disease or oral care agents; diphenhydramine, diphenoxylate, dipyridamole, disopyra amino acids; peptides; dipeptides; tripeptides; glutathione mide, dobutamine, dolfetilide, dolasetron, donepezil, dopa and its derivatives; oligopeptides; polypeptides; carbohy esters, dopamide, dopamine, dorzolamide, doxepin, doxoru drates; aminocarbohydrates; vitamins; corticosteroids; tan bicin, doxycycline, doxylamine, doxepin, dulloxetine, dyclo ning agents; hormones and retinoids. 25 nine, econazole, efalizumab, eflomithine, eletriptan, emitric Non-limiting specific examples of particular cosmetic, itabine, enalapril, ephedrine, epinephrine, epinine, pharmaceutical or other topically active agents, as Stated or as epirubicin, eptifibatide, ergotamine, erythromycin, escitalo free base, free acid, ester, amide, lactone or salt form, include pram, esmolol, esomeprazole, estazolam, estradiol, etaner for synergetic or synergistic effects: abacavir, abciximab, cept, ethacrynic acid, ethinyl estradiol, etidocaine, etomidate, acamprosate, acarbose, acebutolol, acetaminophen, acetami 30 famciclovir, famotidine, felodipine, fentanyl, ferulic acid, noSalol, acetazolamide, acetic acid, acetohydroxamic acid, fexofenadine, flecamide, fluconazole, flucytosine, fluocino N-acetylcysteine and its esters, N-acetylglutathione and its lone acetonide, fluocinonide, 5-fluorouracil, fluoxetine, esters, acitretin, aclometaSone dipropionate, acrivastine, fluphenazine, flurazepam, fluticaSone propionate, fluvoxam acthrel, actidose, actigall, acyclovir, adalimumab, adapalene, ine, formoterol, furosemide, galactarolactone, galactonic adefovir dipivoxil, adenosine, agallsidase, albendazole, albu 35 acid, galactonolactone, galantamine, gatifloxacin, gefitinib, min, albuterol, aldesleukin, alefacept, alemtuzumab, alendr gemcitabine, gemifloxacin, glucarolactone, gluconic acid, onate, alfuzosin, alitretinoin, allantoin, allium, allopurinol, gluconolactone, glucuronic acid, glucuronolactone, glycolic alloxanthine, almotriptan, alosetron, alpha tocopheral, acid, griseofulvin, guaifenesin, guanethidine, N-guanylhista alpha,-proteinase, alprazolam, alprenolol, alprostadil, mine, haloperidol, haloprogin, hexylresorcinol, homatropine, alteplase, altretamine, aluminum acetate, aluminum chloride, 40 homosalate, hydralazine, hydrochlorothiazide, hydrocorti aluminum chlorohydroxide, aluminum hydroxide, amanta Sone, hydrocortisone 21-acetate, hydrocortisone 17-butyrate, dine, amifostine, amiloride, aminacrine, amino acid, ami hydrocortisone 17-Valerate, hydrogen peroxide, hydromor nobenzoate, p-aminobenzoic acid, aminocaproic acid, ami phone, hydroquinone, hydroquinone monoether, hydrox nohippurate, aminolevulinic acid, aminosalicylic acid, yZine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol. amiodarone, amitriptyline, amlodipine, amocarzine, amodi 45 idarubicin, imatinib, imipramine, imiquimod, indinavir, aquin, amorolfine, amoxapine, amoxicillin, amphetamine, indomethacin, infliximab, irbesartan, irinotecan, isoetharine, amphotericin, amplicillin, amprenavir, anagrelide, anakinra, isoproterenol, itraconazole, kanamycin, ketamine, ket anastroZole, anisindione, anthralin, antihemophilic, anti anserin, ketoconazole, ketoprofen, ketotifen, kojic acid, labe thrombin, anti-thymocyte, antivenin, apomorphine, aprepi talol, lactic acid, lactobionic acid, lamivudine, lamotrigine, tant, aprotinin, arbutin, argatroban, aripiprazole, arnica, 50 lansoprazole, letrozole, leuprolide, levalbuterol, levofloxa ascorbic acid and its esters, ascorbyl palmitate, aspirin, ata cin, lidocaine, lineZolid, lobeline, loratadine, loperamide, Zanavir, atenolol, atomoxetine, atorvastatin, atovaquone, losartan, loxapine, lysergic diethylamide, mafenide, malic atropine, azathioprine, azelaic acid, azelastine, azithromycin, acid, maltobionic acid, mandelic acid, maprotiline, mebenda baclofen, bacitracin, balsalazide, balsam, basiliximab, Zole, mecamylamine, meclizine, meclocycline, memantine, beclomethasone dipropionate, bemegride, benazepril, ben 55 menthol, meperidine, mepivacaine, meduinol, mercaptopu droflumethiazide, benzocaine, benzonatate, benzophenone, rine, mescaline, metanephrine, metaproterenol, metaraminol, benzoyl peroxide, benztropine, bepridil, beta carotene, metformin, methadone, methamphetamine, methotrexate, betamethasone dipropionate, betamethasone Valerate, betax methoxamine, methyldopa esters, methyldopamide, olol, bethanechol, bevacizumab, bexarotene, bicalutamide, bimatoprost, bioflavonoids, biotin, biperiden, bisacodyl, 60 3.4-methylenedioxymethamphetamine, methylactic acid, bisoprolol, bivalirudin, bortezomib, bosentan, botulinum, methyl nicotinate, methylphenidate, methyl salicylate, metia brimonidine, brinzolamide, bromocriptine, bromphe mide, metolaZone, metoprolol, metronidazole, mexiletine, niramine, budesonide, bumetanide, bupivacaine, buprenor miconazole, midazolam, midodrine, miglustat, minocycline, phine, bupropion, burimamide, buspirone, buSulfan, butabar minoxidil, mirtazapine, mitoxantrone, moexiprilat, molin bital, butalbital, butenafine, butoconazole, butorphanol, butyl 65 done, monobenzone, morphine, moxifloxacin, moxonidine, aminobenzoate, cabergoline, caffeic acid, caffeine, calcipot mupirocin, nadolol, naftifine, nalbuphine, nalmefene, nalox riene, calcitonin-Salmon, calcitriol, calfactant, camelia sin one, naproxen, nefazodone, nelfinavir, neomycin, nevirapine, US 7,776,844 B2 17 18 nicardipine, nicotine, nifedipine, nimodipine, nisoldipine, ethanol, propylene glycol, butylene glycol, and/or other phar nitrofurantoin, nizatidine, norepinephrine, nystatin, octo maceutically or cosmetically acceptable vehicle. The concen pamine, octreotide, octyl methoxycinnamate, octyl salicy tration of a single N-(phosphonoalkyl)-amino acid, prefer late, ofloxacin, olanzapine, olmesartan medoxomil, olopata ably an N-(phosphonomethyl)-amino acid, a related dine, omeprazole, ondansetron, oxiconazole, oxotremorine, compound or derivative, or the total concentration of all oxybenzone, oxybutynin, oxycodone, oxymetazoline, padi N-(phosphonomethyl)-amino acids where the composition mate O, palonosetron, pantothenic acid, pantoyl lactone, par comprises more than one N-(phosphonomethyl)-amino acid, oxetine, pemoline, penciclovir, penicillamine, penicillins, can be about 0.01% to about 99.9%, with a preferred concen pentazocine, pentobarbital, pentostatin, pentoxifylline, per tration of about 0.1% to about 50%, and a more preferred golide, perindopril, permethrin, phencyclidine, phenelzine, 10 concentration of about 0.5% to about 10%. pheniramine, phenmetrazine, phenobarbital, phenol, phe To prepare a topical composition in lotion, cream or oint noxybenzamine, phentolamine, phenylephrine, phenylpro ment form, the N-(phosphonoalkyl)-amino acid, a related panolamine, phenyloin, physostigmine, pilocarpine, pime compound or derivative of the present invention, preferably crolimus, pimozide, pindolol, pioglitaZone, pipamazine, an N-(phosphonomethyl)-amino acid, is first dissolved in piperonylbutoxide, pirenzepine, podofilox, povidone iodine, 15 water, ethanol, propylene glycol, and/or other vehicle, and the pramipexole, pramoxine, prazosin, prednisone, prenalterol, solution thus obtained is mixed with a desired base or phar prilocalne, procainamide, procaine, procarbazine, pro maceutically or cosmetically acceptable vehicle to make a mazine, promethazine, promethazine propionate, pro lotion, cream or ointment. Typical ointments can be made pafenone, propoxyphene, propranolol, propylthiouracil, pro readily with an oil-in-water emulsion, such as hydrophilic triptyline, pseudoephedrine, pyrethrin, pyrilamine, ointment U.S.P., as is well known to those skilled in the art in pyrimethamine, quetiapine, quinapril, quinethaZone, quini view of the present disclosure. Concentrations of the dine, quinupristin, rabeprazole, reserpine, resorcinol, retinal, N-(phosphonoalkyl)-amino acid are the same as described 13-cis retinoic acid, retinoic acid, retinol, retinyl acetate, retinyl palmitate, ribavirin, ribonic acid, ribonolactone, above regarding Solutions. rifampin, rifapentine, rifaximin, riluzole, rimantadine, 25 A topical composition of the instant invention can also be risedronic acid, risperidone, ritodrine, rivastigmine, rizatrip formulated in a gel or shampoo form. A typical gel composi tan, ropinirole, ropivacaine, salicylamide, Salicylic acid, sal tion is formulated by the addition of a gelling agent such as meterol, Scopolamine, selegiline, selenium sulfide, serotonin, chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, Sertaconazole, sertindole, Sertraline, shale tar, Sibutramine, polyduatemiums, hydroxyethylcellulose, hydroxypropylcel sildenafil. Sotalol, Streptomycin, Strychnine, Sulconazole, Sul 30 lulose, hydroxypropylmethylcellulose, carbomer or ammoni facetamide, Sulfabenz, Sulfabenzamide, SulfabromomethaZ ated glycyrrhizinate to a solution comprising the ine, sulfacetamide(sodium sulfacetamide), sulfachlorpy N-(phosphonoalkyl)-amino acid. The preferred concentra ridazine, Sulfacytine, Sulfadiazine, Sulfadimethoxine, tion of the gelling agent may be about 0.1% to about 4%. In Sulfadoxine, Sulfaguanole, Sulfalene, Sulfamethizole, Sul the preparation of shampoo, the N-(phosphonoalkyl)-amino famethoxazole, Sulfanilamide, Sulfapyrazine, Sulfapyridine, 35 acid, related compound or derivative thereof is first dissolved Sulfasalazine, Sulfasomizole, Sulfathiazole, Sulfisoxazole, in water or propylene glycol, and the solution thus obtained is Sulfur, tacrolimus, tadalafil, tamsulosin, tartaric acid, tazaro mixed with a shampoo base. Concentrations of the tene, tegaserod, tellithromycin, telmisartan, temozolomide, N-(phosphonoalkyl)-amino acid, related compound or tenofovir disoproxil, terazosin, terbinafine, terbutaline, ter derivative thereofused ingel or shampoo form are the same as conazole, terfenadine, tetracaine, tetracycline, tetrahydroZo 40 described above regarding solutions. line, thalidomide, theobromine, theophylline, thiabendazole, To prepare a combination composition for synergetic or thioctic acid (lipoic acid), thioridazine, thiothixene, thymol. synergistic effects, a cosmetic, pharmaceutical or other agent tiagabine, timolol, timidazole, tioconazole, tirofiban, tizani is incorporated into any one of the above compositions by dine, tobramycin, tocamide, tolazoline, tolbutamide, tolnaf dissolving or mixing the agent into the formulation. Other tate, tolterodine, tramadol, tranylcypromine, traZodone, tri 45 forms of compositions of the present invention for delivery of amcinolone acetonide, triamcinolone diacetate, the N-(phosphonoalkyl)-amino acid, a related compound or triamcinolone hexacetonide, triamterene, triazolam, tri derivative of the present invention, preferably an closan, triflupromazine, trimethoprim, trimipramine, tripe N-(phosphonomethyl)-amino acid, are readily blended, pre lennamine, triprolidine, tromethamine, tropic acid, tyramine, pared or formulated by those skilled in the art in view of the undecylenic acid, urea, urocanic acid, ursodiol, Valacyclovir, 50 present disclosure. For systemic administration the Vardenafil. Venlafaxine, Verapamil, vitamin E acetate, Vori N-(phosphonoalkyl)-amino acid, a related compound or conazole, warfarin, wood tar, Xanthine, Zafirlukast, Zaleplon, derivative of the present invention, preferably an Zinc pyrithione, Ziprasidone, Zolmitriptan and Zolpidem. N-(phosphonomethyl)-amino acid, can beformulated for oral General Preparations administration or for parenteral injection or infusion. In oral Compositions of the present invention comprising an 55 preparations, the N-(phosphonoalkyl)-amino acid can be for N-(phosphonoalkyl)-amino acid, preferably an N-(phospho mulated in tablet form or in gelatin capsules with or without nomethyl)-amino acid, a related compound or derivative of mixing with gelatin powder. Each tablet or capsule can con the present invention can be formulated as an injectable or tain about 10 mg to about 300 mg of the N-(phosphonom infusible solution or otherformulation oras a topical solution, ethyl)-amino acid as free acid, salt, amide, ester or lactone gel, lotion, cream, ointment, shampoo, spray, Stick, pad, pow 60 form. For parenteral injection or infusion, the N-(phospho der, masque, mouth rinse or wash, vaginal gel or preparation, nomethyl)-amino acid is prepared under sterilized condi or other form acceptable for use on skin, nail, hair, oral tions, usually in a concentration of about 1% to about 10% in mucosa, Vaginal or anal mucosa, mouth or gums. water, propylene glycol and/or non-aqueous vehicle. To prepare a solution composition of the present invention, The present invention will now be described in more detail at least one N-(phosphonoalkyl)-amino acid, preferably an 65 with reference to the following non-limiting examples. In the N-(phosphonomethyl)-amino acid, a related compound or initial tests for comparative studies, a control vehicle was derivative is dissolved in a solution prepared from water, always included. It was discovered that all the vehicle con US 7,776,844 B2 19 20 trols gave the same results as that of the untreated skin sites: ment in contrast to the untreated or vehicle control as judged no detectable effects of the controls have been found as by clinical evaluation. After two weeks oftopical application, judged by clinical evaluation. the scales disappeared completely and the treated skin For subjective disorders such as pain, itch or the like, the became smooth, and had 90% improvement in contrast to the therapeutic effects were evaluated or judged by the subjects or untreated or vehicle control as judged by clinical evaluation. patients; for example, if the pain or itch had disappeared The above results show that another representative within hours or days. For other detectable symptoms or syn N-(phosphonomethyl)-amino acid would be therapeutically dromes, the therapeutic effects or improvements were evalu effective for topical treatment of disturbed keratinization and ated or judged by medical professionals. hyperkeratotic conditions including dry skin, severe dry skin, 10 ichthyosis, calluses, keratoses, acne, rosacea, blemished skin, EXAMPLE1 psoriasis and age spots. In one of the studies related to skin changes associated with EXAMPLE 4 aging, skin thickness was measured by micrometer calipers as follows: 15 N-(phosphonomethyl)-glycine ethyl ester (5 g) was dis The skin was grasped with a 2x6 cm metal hinge, the solved in warm water (20 ml) and propylene glycol (20 ml), internal faces of which were coated with emery cloth to and the solution thus obtained was mixed with hydrophilic prevent slippage, and manually Squeezed to threshold subject ointment (oil-in-water emulsion, 55 g). The white cream thus discomfort. Combined thickness of two whole-skin layers formulated had pH 1.2 and contained 5% N-(phosphonom including thickness of the two hinge leaves was measured ethyl)-glycine ethyl ester. with micrometer calipers. Thickness of the two hinge leaves A male Subject, age 86, had chronic plaque psoriasis with was subtracted to determine the actual thickness of the two erythema, moderately thick and silvery scales. The subject whole-skin layers. Triplicate measurements on treated sites topically applied twice daily the above white cream contain were done and an average number was used for calculation of ing 5% N-(phosphonomethyl)-glycine ethyl ester to one pso the skin thickness. 25 riatic lesion for two weeks. At the end of two weeks, the erythema and silvery scales improved Substantially, and the EXAMPLE 2 treated skin had 50% improvement in contrast to the untreated or vehicle control as judged by clinical evaluation. N-(phosphonomethyl)-glycine (5 g) was suspended in water (30 ml) and propylene glycol (10 ml), and concentrated 30 EXAMPLE 5 ammonium hydroxide (2 ml) was added with stirring. The suspension became a clear solution, and was mixed with N-(phosphonomethyl)-L-tyrosine (5 g) was dissolved in hydrophilic ointment (oil-in-water emulsion, 53 g). The warm propylene glycol (40 ml), and the solution thus white cream thus formulated had pH 3.8 and contained 5% obtained was mixed with hydrophilic ointment (oil-in-water N-(phosphonomethyl)-glycine. A male Subject, age 35, who 35 emulsion, 55 g). The white cream thus formulated had pH 2.3 had X-linked ichthyosis with severe dry skin, having thick and contained 5% N-(phosphonomethyl)-L-tyrosine. and rough skin with adherent scales, topically applied the A male subject, age 35, who had X-linked ichthyosis with above 5% N-(phosphonomethyl)-glycine cream to an severe dry skin, having thick and rough skin with adherent involved skin site twice daily for two weeks. After one week scales, topically applied the above 5% N-(phosphonom of topical application, the adherent scales disappeared, and 40 ethyl)-L-tyrosine cream to an involved skin site twice daily the skin became smooth and had 50% improvement in con for 12 days. After 12 days of topical application, most adher trast to the untreated or vehicle control as judged by clinical ent scales disappeared and the skin became Smooth, and had evaluation. After two weeks oftopical application, the treated 75% improvement in contrast to the untreated or vehicle skin became normal in appearance, and had 100% improve control as judged by clinical evaluation. ment in contrast to the untreated or vehicle control as judged 45 The above results show that another representative by clinical evaluation. The above results show that a repre N-(phosphonomethyl)-amino acid would be therapeutically sentative N-(phosphonomethyl)-amino acid would be thera effective for topical treatment of disturbed keratinization and peutically effective for topical treatment of disturbed kerati hyperkeratotic conditions including dry skin, severe dry skin, nization and hyperkeratotic conditions including dry skin, ichthyosis, calluses, keratoses, acne, rosacea, blemished skin, severe dry skin, ichthyosis, calluses, keratoses, acne, rosacea, 50 psoriasis and age spots. blemished skin, psoriasis and age spots. EXAMPLE 6 EXAMPLE 3 N-(phosphonomethyl)-L-proline (5 g) was suspended in N-(phosphonomethyl)imino-diacetic acid (5 g) was sus 55 water (20 ml), and concentrated ammonium hydroxide (0.8 pended in water (15 ml) and propylene glycol (10 ml), and ml) was added. The solution thus obtained was mixed with concentrated ammonium hydroxide (3 ml) was added with hydrophilic ointment (oil-in-water emulsion, 74.2 g). The stirring. The Suspension became a clear Solution, and was white cream thus formulated had pH 3.2 and contained 5% mixed with hydrophilic ointment (oil-in-water emulsion 67 N-(phosphonomethyl)-L-proline. Under the same procedure, g). The white cream thus formulated had pH 3.5 and con 60 a white cream containing 10% N-(phosphonomethyl)-L-pro tained 5% N-(phosphonomethyl)imino-diacetic acid. line was formulated from N-(phosphonomethyl)-L-proline A male subject, age 35, who had X-linked ichthyosis with (10g), water (20 ml), concentrated ammonium hydroxide (1 severe dry skin, having thick and rough skin with adherent ml), and hydrophilic ointment (oil-in-water emulsion, 69 g). scales, topically applied the above 5% N-(phosphonomethyl) A male Subject, age 86, had chronic plaque psoriasis with imino-diacetic acid cream to an involved skin site twice daily 65 erythema, moderately thick and silvery scales. The subject for two weeks. After one week of topical application, most topically applied twice daily the above white cream contain adherent scales disappeared and the skin had 50% improve ing 10% N-(phosphonomethyl)-L-proline to one psoriatic US 7,776,844 B2 21 22 lesion for two weeks. At the end of two weeks, the erythema 2-amino-2-methyl-1-propanol (5 ml). The clear solution thus and silvery scales improved very Substantially, and the treated obtained was mixed with hydrophilic ointment (oil-in-water skin had 75% improvement in contrast to the untreated or emulsion, 55 g). The white cream thus formulated had pH 5.1, vehicle control as judged by clinical evaluation. and contained 10% N-(phosphonomethyl)-glycine propyl The above results show that yet another representative ester. Under the same procedure, a white cream containing N-(phosphonomethyl)-amino acid would be therapeutically 5% N-(phosphonomethyl)-glycine propyl ester was formu effective for topical treatment of disturbed keratinization and lated from N-(phosphonomethyl)-glycine propyl ester (5 g), inflammatory conditions including erythema, eczema, der warm water (20 ml), propylene glycol (10 ml), 2-amino-2- matitis, dermatoses, itch, psoriasis, acne and rosacea. methyl-1-propanol (2.5 ml) and hydrophilic ointment (oil-in 10 water emulsion, 62.5 g). EXAMPLE 7 A male Subject, age 86, had chronic plaque psoriasis with erythema, moderately thick and silvery scales. The subject N-(phosphonomethyl)-DL-asparagine (6 g) was dissolved topically applied twice daily the above white cream contain in warm water (30 ml) and propylene glycol (10 ml), and the ing 5% N-(phosphonomethyl)-glycine propyl ester to one solution thus obtained was mixed with hydrophilic ointment 15 psoriatic lesion for two weeks. At the end of two weeks, the (oil-in-water emulsion, 54 g). The white cream thus formu erythema and silvery scales improved very Substantially, and lated had pH 2.2 and contained 6% N-(phosphonomethyl)- the treated skin had 75% improvement in contrast to the DL-asparagine. untreated or vehicle control as judged by clinical evaluation. N-(phosphonomethyl)-DL-asparagine (5 g) was dissolved The above results show that still another representative in warm water (30 ml) and propylene glycol (10 ml), and the N-(phosphonomethyl)-amino acid derivative would be thera solution thus obtained was mixed with hydrophilic ointment peutically effective for topical treatment of disturbed kerati (oil-in-water emulsion, 55 g). The white cream thus formu nization and inflammatory conditions including erythema, lated had pH 2.2 and contained 5% N-(phosphonomethyl)- eczema, dermatitis, dermatoses, itch, psoriasis, acne and DL-asparagine. OSaCCa. A male subject, age 36, who had X-linked ichthyosis hav 25 ing thick and rough skin with adherent scales, topically applied the 5% N-(phosphonomethyl)-DL-asparagine cream EXAMPLE 10 to an involved skin site twice daily for three weeks. After one week of topical application, most adherent scales disappeared N-(phosphonomethyl)-glycine isopropyl ester (10 g) was and the treated site appeared smooth. The skin had 75% 30 dissolved in water (10 ml), propylene glycol (20 ml) and improvement in contrast to the untreated or vehicle control as meglumine (N-methyl-D-glucamine, 4 g). The Solution thus judged by clinical evaluation. After three weeks of topical obtained was mixed with hydrophilic ointment (oil-in-water application, the scales disappeared completely and the treated emulsion, 56 g). The white cream thus formulated had pH 1.1, site felt smooth and normal inappearance. The skin had 100% and contained 10% N-(phosphonomethyl)-glycine isopropyl improvement in contrast to the untreated or vehicle control as 35 ester. Under the same procedure, a white cream containing judged by clinical evaluation. 5% N-(phosphonomethyl)-glycine isopropyl ester was for The above results show that another N-(phosphonom mulated from N-(phosphonomethyl)-glycine isopropyl ester ethyl)-amino acid would be therapeutically effective for topi (5 g), water (10 ml), propylene glycol (20 ml), meglumine (2 cal treatment of disturbed keratinization and hyperkeratotic g) and hydrophilic ointment (63 g). conditions including dry skin, severe dry skin, ichthyosis, 40 A male Subject, age 86, had chronic plaque psoriasis with calluses, keratoses, acne, rosacea, blemished skin, psoriasis erythema, moderately thick and silvery scales. The subject and age spots. topically applied twice daily the above white cream contain ing 5% N-(phosphonomethyl)-glycine isopropyl ester to one EXAMPLE 8 psoriatic lesion for a week. At the end of one week, the 45 erythema and silvery scales improved Substantially, and the A male Subject, age 36, who had hyperpigmented dark treated skin had 50% improvement in contrast to the untreated skin, topically applied 5% N-(phosphonomethyl)-DL-aspar or vehicle control as judged by clinical evaluation. agine cream prepared according to Example 7 to an involved skin site twice daily for four weeks. After two weeks of EXAMPLE 11 topical application, the treated site had mild depigmentation 50 and showed lighter skin color as compared to untreated skin N-(phosphonomethyl)-glycinamide (5 g) was dissolved in site. The treated site was 25% lighter in skin color in contrast water (10 ml) and propylene glycol (30 ml), and the mixture to the untreated or vehicle control as judged by clinical evalu thus obtained was mixed with hydrophilic ointment (oil-in ation. After four weeks of topical application, the treated site water emulsion, 55 g). The white cream thus formulated had had substantial reduction in skin pigmentation. The treated 55 pH 2.1 and contained 5% N-(phosphonomethyl)-glycina site was 50% lighter in contrast to the untreated or vehicle mide. Under the same procedure, a white cream containing control in skin color as judged by clinical evaluation. 8% N-(phosphonomethyl)-glycinamide was formulated from The above results show that a representative N-(phospho N-(phosphonomethyl)-glycinamide (8 g), water (10 ml), pro nomethyl)-amino acid would be effective for topical treat pylene glycol (30 ml) and hydrophilic ointment (52 g). ment of hyperpigmented skin, age spots, melasma, lentigines, 60 A male Subject, age 86, had chronic plaque psoriasis with mottled skin, aging related skin changes, and would be topi erythema, moderately thick and silvery scales. The subject cally effective for skin lightening. topically applied twice daily the above white cream contain ing 8% N-(phosphonomethyl)-glycinamide to one psoriatic EXAMPLE 9 lesion for three weeks. At the end of three weeks, the 65 erythema and silvery scales disappeared almost completely, N-(phosphonomethyl)-glycine propyl ester (10 g) was dis and the treated skin had 90% improvement in contrast to the solved in warm water (20 ml), propylene glycol (10 ml) and untreated or vehicle control as judged by clinical evaluation. US 7,776,844 B2 23 24 The above results show that another representative and the treated skin had 70% improvement in contrast to the N-(phosphonomethyl)-amino acid derivative would be thera untreated or vehicle control as judged by clinical evaluation. peutically effective for topical treatment of disturbed kerati nization and inflammatory conditions including erythema, EXAMPLE 1.4 eczema, dermatitis, dermatoses, itch, psoriasis, acne and OSaCCa. N-(phosphonomethyl)-L-serine (6 g) was dissolved in warm propylene glycol (10 ml) and water (30 ml). The solu EXAMPLE 12 tion thus obtained was mixed with hydrophilic ointment (oil in-water emulsion, 54 g). The white cream thus formulated 10 had pH 1.7 and contained 6% N-(phosphonomethyl)-L- N-(phosphonomethyl)-L-tyrosine ethyl ester (5 g) was dis serine. solved in warm propylene glycol (20 ml) and water (10 ml). The solution thus obtained was mixed with hydrophilic oint EXAMPLE 1.5 ment (oil-in-water emulsion, 65 g). The white cream thus formulated had pH 1.2 and contained 5% N-(phosphonom 15 N-(phosphonomethyl)-L-proline ethyl ester (8 g) was dis ethyl)-L-tyrosine ethyl ester. solved in water (10 ml), propylene glycol (20 ml) and ethyl A male subject, age 36, who had X-linked ichthyosis hav enediamine (4 ml). The solution thus obtained was mixed ing thick and rough skin with adherent scales, topically with hydrophilic ointment (oil-in-water emulsion, 58 g). The applied the above 5% N-(phosphonomethyl)-L-tyrosine ethyl white cream thus formulated had pH 5.9, and contained 8% ester cream to an involved skin site twice daily for one week. N-(phosphonomethyl)-L-proline ethyl ester. After one week of topical application, most adherent scales A male Subject, age 74, having itchy eczema on his right disappeared and the treated skin had 25% improvement in thigh, topically applied the above 8% N-(phosphonomethyl)- contrast to the untreated or vehicle control as judged by L-proline ethyl ester cream. The itch disappeared within a few clinical evaluation. minutes after the topical application. The treated skin did not 25 itch for the next 8 hours. Therapeutic evaluation was judged to The above results show that another N-(phosphonom be 100% effective in contrast to the untreated or vehicle ethyl)-amino acid would be therapeutically effective for topi control for immediate relief of itch. cal treatment of disturbed keratinization and hyperkeratotic The above result shows that a representative N-(phospho conditions including dry skin, severe dry skin, ichthyosis, nomethyl)-amino acid derivative would be therapeutically calluses, keratoses, acne, rosacea, blemished skin, psoriasis 30 effective for topical treatment of disturbed keratinization and and age spots. inflammatory conditions including erythema, eczema, der A male Subject, age 86, had chronic plaque psoriasis with matitis, dermatoses, itch, psoriasis, acne and rosacea. erythema, moderately thick and silvery scales. The subject topically applied twice daily the above white cream contain EXAMPLE 16 ing 5% N-(phosphonomethyl)-L-tyrosine ethyl ester to one 35 psoriatic lesion for two weeks. At the end of two weeks, the N-(phosphonomethyl)-L-serine ethyl ester (6 g) was dis erythema and silvery scales improved noticeably and the solved in warm propylene glycol (30 ml). The solution thus treated skin had 25% improvement in contrast to the untreated obtained was mixed with hydrophilic ointment (oil-in-water or vehicle control as judged by clinical evaluation. 40 emulsion, 64 g). The white cream thus formulated had pH 1.3 The above results show that another representative and contained 6% N-(phosphonomethyl)-L-serine ethyl N-(phosphonomethyl)-amino acid derivative would be thera ester. peutically effective for topical treatment of disturbed kerati nization and inflammatory conditions including erythema, EXAMPLE 17 eczema, dermatitis, dermatoses, itch, psoriasis, acne and 45 OSaCCa. N-(phosphonomethyl)-creatine (7 g) was dissolved in water (30 ml) and propylene glycol (10 ml), and the solution EXAMPLE 13 thus obtained was mixed with hydrophilic ointment (oil-in water emulsion, 53 g). The white cream thus formulated had 50 pH 1.8 and contained 7% N-(phosphonomethyl)-creatine. N-(phosphonomethyl)-D-4-hydroxyphenylglycine (5 g) Under the same procedure, a white cream containing 5% was dissolved in water (10 ml) and propylene glycol (20 ml), N-(phosphonomethyl)-creatine was formulated from and the mixture thus obtained was mixed with hydrophilic N-(phosphonomethyl)-creatine (5 g), water (30 ml), propy ointment (oil-in-water emulsion, 65 g). The white cream thus lene glycol (10 ml), and hydrophilic ointment or oil-in-water formulated had pH 2.4, and contained 5% N-(phosphonom 55 emulsion (55 g). Under the same procedure, a white cream ethyl)-D-4-hydroxyphenylglycine. Under the same proce containing 10% N-(phosphonomethyl)-creatine was formu dure, a white cream containing 10% N-(phosphonomethyl)- lated from N-(phosphonomethyl)-creatine (10 g), water (30 D-4-hydroxyphenylglycine was formulated from ml), propylene glycol (10 ml), and hydrophilic ointment (oil N-(phosphonomethyl)-D-4-hydroxyphenylglycine (10 g). in-water emulsion, 50 g). water (10 ml), propylene glycol (20 ml), and hydrophilic 60 A male Subject, age 86, had chronic plaque psoriasis with ointment (60 g). erythema, moderately thick and silvery scales. The subject A male Subject, age 86, had chronic plaque psoriasis with topically applied twice daily the above white cream contain erythema, moderately thick and silvery scales. The subject ing 5% N-(phosphonomethyl)-creatine to one psoriatic lesion topically applied twice daily the above white cream contain for two weeks. At the end of two weeks, the erythema and ing 10% N-(phosphonomethyl)-D-4-hydroxyphenylglycine 65 silvery scales improved substantially, and the treated skin had to one psoriatic lesion for two weeks. At the end of two weeks, 50% improvement in contrast to the untreated or vehicle the erythema and silvery scales improved very Substantially, control as judged by clinical evaluation. US 7,776,844 B2 25 26 EXAMPLE 1.8 Volume), ethanol (40 parts by Volume) and propylene glycol (20 parts by volume). The composition thus prepared had 2.7, A male Subject, age 74, having itchy eczema on his left leg, and contained 5% N-(phosphonomethyl)-DL-asparagine in topically applied 7% N-(phosphonomethyl)-creatine cream Solution. prepared according to Example 17. The itch disappeared A male Subject, age 36, who had hyperpigmented dark within a few minutes after the topical application. The treated skin, topically applied the above 5% N-(phosphonomethyl)- skin did not itch for the next 8 hours. Therapeutic evaluation DL-asparagine solution to an involved skin site once every was judged to be 100% effective in contrast to the untreated or other day with occlusion for ten days. After seven days of vehicle control for immediate relief of itch. topical application, the treated site had mild depigmentation The above results show that a representative N-(phospho 10 and showed lighter skin color as compared to untreated skin nomethyl)-amino acid would be therapeutically effective for site. The treated site was 25% lighter in skin color as judged topical treatment of disturbed keratinization and inflamma by clinical evaluation. After ten days of topical application, tory conditions including erythema, eczema, dermatitis, der the treated site had substantial reduction in skin pigmentation. matoses, itch, psoriasis, acne and rosacea. The treated site was 50% lighter in skin color in contrast to the 15 untreated or vehicle control as judged by clinical evaluation. EXAMPLE19 The above results show that a representative N-(phospho nomethyl)-amino acid would be effective for topical treat N-(phosphonomethyl)-creatine (2 g) was dissolved in (98 ment of hyperpigmented skin, age spots, melasma, lentigines, ml) of a solution prepared from water (40 parts by volume), mottled skin, aging related skin changes, and would be topi ethanol (40 parts by Volume) and propylene glycol (20 parts cally effective for skin lightening. by volume). The composition thus prepared had pH 2.5 and contained 2% N-(phosphonomethyl)-creatine in solution. EXAMPLE 22 N-(phosphonomethyl)-creatine (5 g) was dissolved in (95 ml) solution prepared from water (40 parts by volume), etha A male subject, age 36, who had X-linked ichthyosis hav nol (40 parts by volume) and propylene glycol (20 parts by 25 ing thick and rough skin with adherent scales, topically volume). The composition thus prepared contained 5% applied the 5% N-(phosphonomethyl)-DL-asparagine solu N-(phosphonomethyl)-creatine in solution. tion prepared according to Example 21 to an involved skin A male subject, age 35, who had X-linked ichthyosis hav site once every other day under occlusion for three weeks. ing thick and rough skin with adherent scales, topically After one week of topical application, most adherent scales applied the above 5% N-(phosphonomethyl)-creatine solu 30 disappeared and the treated site appeared Smooth. The skin tion to an involved skin site once every other with occlusion had 75% improvement in contrast to the untreated or vehicle for two weeks. After 10 days of topical application, most control as judged by clinical evaluation. After three weeks of adherent scales disappeared and the skin had 50% improve topical application, the treated skin site appeared normal, and ment in contrast to the untreated or vehicle control as judged the skin had 100% improvement in contrast to the untreated or by clinical evaluation. After two weeks oftopical application, 35 vehicle control as judged by clinical evaluation. the scales disappeared completely and the treated skin The above results show that a representative N-(phospho became normal in appearance, and had 100% improvement in nomethyl)-amino acid would be therapeutically effective for contrast to the untreated or vehicle control as judged by topical treatment of disturbed keratinization and hyperkera clinical evaluation. totic conditions including dry skin, severe dry skin, ichthyo The above results show that another representative 40 N-(phosphonomethyl)-amino acid would be therapeutically sis, calluses, keratoses, acne, rosacea, blemished skin, pso effective for topical treatment of disturbed keratinization and riasis and age spots. hyperkeratotic conditions including dry skin, severe dry skin, ichthyosis, calluses, keratoses, acne, rosacea, blemished skin, EXAMPLE 23 psoriasis and age spots. 45 N-(phosphonomethyl)-creatine (5 g) was dissolved in (95 EXAMPLE 20 ml) solution prepared from water (40 parts by volume), etha nol (40 parts by volume) and propylene glycol (20 parts by N-(phosphonomethyl)-tyramine (5 g) was Suspended in volume). The composition thus prepared had pH 2.5, and warm propylene glycol (30 ml), and water (5 ml), and the 50 contained 5% N-(phosphonomethyl)-creatine in solution. mixture thus obtained was mixed with hydrophilic ointment A male Subject, age 36, who had hyperpigmented dark (oil-in-water emulsion, 60 g). The white cream thus formu skin, topically applied the above 5% N-(phosphonomethyl)- lated had pH 2.1 and contained 5% N-(phosphonomethyl)- creatine solution to an involved skin site once every other day tyramine. with occlusion for two weeks. After seven days of topical A male Subject, age 86, had chronic plaque psoriasis with 55 application, the treated site had mild depigmentation and erythema, moderately thick and silvery scales. The subject showed lighter skin color as compared to untreated skin site. topically applied twice daily the above white cream contain The treated site was 25% lighter in skin color in contrast to the ing 5% N-(phosphonomethyl)-tyramine to one psoriatic untreated or vehicle control as judged by clinical evaluation. lesion for two weeks. At the end of two weeks, the erythema After two weeks of topical application, the treated site had and silvery scales improved Substantially, and the treated skin 60 very Substantial reduction in skin pigmentation. The treated had 50% improvement in contrast to the untreated or vehicle site was 75% lighter in skin color in contrast to the untreated control as judged by clinical evaluation. or vehicle control as judged by clinical evaluation. The above results show that a representative N-(phospho EXAMPLE 21 nomethyl)-amino acid would be effective for topical treat 65 ment of hyperpigmented skin, age spots, melasma, lentigines, N-(phosphonomethyl)-DL-asparagine (5 g) was dissolved mottled skin, aging related skin changes, and would be topi in (95 ml) of a solution prepared from water (40 parts by cally effective for skin lightening. US 7,776,844 B2 27 28 EXAMPLE 24 melasma, lentigines, mottled skin, aging related skin changes, and would be topically effective for skin lightening. N-(phosphonomethyl)-glycinamide (5 g) was dissolved in (95 ml) of a solution prepared from water (40 parts by vol EXAMPLE 27 ume), ethanol (40 parts by Volume) and propylene glycol (20 parts by volume). The composition thus prepared had pH 2.5, A male subject, age 36, who had X-linked ichthyosis hav and contained 5% N-(phosphonomethyl)-glycinamide in ing thick and rough skin with adherent scales, topically Solution. applied 5% N-(phosphonomethyl)-L-glutamine solution pre A male Subject, age 36, who had hyperpigmented dark pared according to Example 26 to an involved skin site once skin, topically applied the above 5% N-(phosphonomethyl)- 10 every other day for three weeks. After two weeks of topical glycinamide solution to an involved skin site once every other application, most scales disappeared and the treated site felt day with occlusion for two weeks. After seven days oftopical nearly smooth, and the skin had 75% improvement in contrast application, the treated site had mild depigmentation and to the untreated or vehicle control as judged by clinical evalu showed lighter skin color as compared to untreated skin site. ation. After three weeks of topical application, the treated site 15 appeared normal, and the skin had 100% improvement in The treated site was 25% lighter in skin color in contrast to the contrast to the untreated or vehicle control as judged by untreated or vehicle control as judged by clinical evaluation. clinical evaluation. After two weeks of topical application, the treated site had The above results show that another representative Substantial reduction in skin pigmentation. The treated site N-(phosphonomethyl)-amino acid would be therapeutically was 50% lighter in skin color in contrast to the untreated or effective for topical treatment of disturbed keratinization and vehicle control as judged by clinical evaluation. hyperkeratotic conditions including dry skin, severe dry skin, The above results show that another representative ichthyosis, calluses, keratoses, acne, rosacea, blemished skin, N-(phosphonomethyl)-amino acid derivative would be effec psoriasis and age spots. tive for topical treatment of hyperpigmented skin, age spots, melasma, lentigines, mottled skin, aging related skin EXAMPLE 28 changes, and would be topically effective for skin lightening. 25 N-(phosphonomethyl)-tyramine (5 g) and concentrated EXAMPLE 25 ammonium hydroxide solution (1 ml) were dissolved in a solution (94 ml) prepared from water (40 parts by volume), A male subject, age 36, who had X-linked ichthyosis hav ethanol (40 parts by Volume) and propylene glycol (20 parts ing thick and rough skin with adherent scales, topically 30 by volume). The composition thus prepared had pH 7.1 and applied 5% N-(phosphonomethyl)-glycinamide Solution pre contained 5% N-(phosphonomethyl)-tyramine in solution. pared according to Example 24 to an involved skin site once A male subject, age 36, who had X-linked ichthyosis hav every other day for three weeks. After one week of topical ing thick and rough skin with adherent scales, topically application, most adherent scales disappeared and the treated applied the above 5% N-(phosphonomethyl)-tyramine solu site appeared smooth. The skin had 75% improvement in 35 tion to an involved skin site once every other day under contrast to the untreated or vehicle control as judged by occlusion for a week. After one week of topical application, clinical evaluation. After three weeks of topical application, most adherent scales disappeared and the treated site the treated skin site appeared normal, and the skin had 100% appeared smooth. The skin had 75% improvement in contrast improvement in contrast to the untreated or vehicle control as to the untreated or vehicle control as judged by clinical evalu judged by clinical evaluation. 40 ation. The above results show that another N-(phosphonom The above results show that another representative ethyl)-amino acid derivative would be therapeutically effec N-(phosphonomethyl)-amino acid would be therapeutically tive for topical treatment of disturbed keratinization and effective for topical treatment of disturbed keratinization and hyperkeratotic conditions including dry skin, severe dry skin, hyperkeratotic conditions including dry skin, severe dry skin, ichthyosis, calluses, keratoses, acne, rosacea, blemished skin, 45 ichthyosis, calluses, keratoses, acne, rosacea, blemished skin, psoriasis and age spots. psoriasis and age spots. EXAMPLE 29 EXAMPLE 26 50 N-(phosphonomethyl)-glutamine (3 g) was dissolved in N-(phosphonomethyl)-L-glutamine (5 g) was dissolved in (97 ml) of a solution prepared from water (80 parts by vol (95 ml) of a solution prepared from water (40 parts by vol ume) and propylene glycol (20 parts by Volume). The com ume), ethanol (40 parts by Volume) and propylene glycol (20 position thus prepared had pH 2.0 and contained 3% parts by volume). The composition thus prepared had pH 2.0, N-(phosphonomethyl)-L-glutamine in Solution. and contained 5% N-(phosphonomethyl)-L-glutamine in 55 N-(phosphonomethyl)-L-glutamine (10 g) was dissolved Solution. in warm water (20 ml) and propylene glycol (10 ml), and the A male Subject, age 36, who had hyperpigmented dark solution thus obtained was mixed with hydrophilic ointment skin, topically applied the above 5% N-(phosphonomethyl)- (oil-in-water emulsion, 60 g). The white cream thus formu L-glutamine solution to an involved skin site once every other lated had pH 1.3 and contained 10% N-(phosphonomethyl)- day with occlusion for two weeks. After two weeks oftopical 60 L-glutamine. application, the treated site had substantial reduction in skin A male Subject, age 74, having itchy eczema on his left pigmentation. The treated site had 50% lighter in skin color in thigh, topically applied the above 10% N-(phosphonom contrast to the untreated or vehicle control as judged by ethyl)-glutamine. The itch disappeared within a few minutes clinical evaluation. after the topical application. The treated skin did not itch for The above result shows that another representative 65 the next 8 hours. Therapeutic evaluation was judged to be N-(phosphonomethyl)-amino acid would be effective for 100% effective in contrast to the untreated or vehicle control topical treatment of hyperpigmented skin, age spots, for immediate relief of itch. US 7,776,844 B2 29 30 The above results show that a representative N-(phospho ml) prepared from water (80 parts by volume) and propylene nomethyl)-amino acid would be therapeutically effective for glycol (20 parts by Volume). The composition thus prepared topical treatment of disturbed keratinization and inflamma had pH 2.1, and contained 1% N-(phosphonomethyl)-guani tory conditions including erythema, eczema, dermatitis, der dinoacetic acid in Solution. matoses, itch, psoriasis, acne and rosacea. EXAMPLE 36 EXAMPLE 30 The following is a typical process for preparing a compo N-(phosphonomethyl)-L-glutamine (6 g) was dissolved in sition comprising an N-(phosphonomethyl)-amino acid or warm water (40 ml), and the solution thus obtained was mixed 10 derivative for oral administration. with hydrophilic ointment (oil-in-water emulsion, 54 g). The N-(Phosphonomethyl)-glycine crystals were converted to white cream thus formulated had pH 1.5 and contained 6% fine powder by grinding with mortar and pestle. Lilly(R) gela N-(phosphonomethyl)-L-glutamine. tin capsules size No. 1, were filled to the top with N-(phosphonomethyl)-glycine powder without mixing with EXAMPLE 31 gelatin powder. Each capsule thus prepared contained 300 mg 15 N-(phosphonomethyl)-glycine. N-(phosphonomethyl)-L-glutamic acid (8 g) was dis A Subject can take orally one or two capsules per day for solved in water (20 ml) and propylene glycol (10 ml), and the systemic administration to alleviate or improve cosmetic con solution thus obtained was mixed with hydrophilic ointment ditions, or medical disorders, symptoms or syndromes asso (oil-in-water emulsion, 62 g). The white cream thus formu ciated with the nervous, vascular, musculoskeletal or cutane lated had pH 2.4 and contained 8% N-(phosphonomethyl)-L- ous system, or others. glutamic acid. A male Subject, age 86, had chronic plaque psoriasis with EXAMPLE 37 erythema, moderately thick and silvery scales. The subject topically applied twice daily the above white cream contain N-(Phosphonomethyl)-L-tyrosine crystals were converted ing 8% N-(phosphonomethyl)-L-glutamic acid to one psori 25 to fine powder by grinding with mortar and pestle. Lilly(R) atic lesion for two weeks. At the end of two weeks, the gelatin capsules size No. 1, were filled to the top with erythema and silvery scales improved Substantially and the N-(phosphonomethyl)-L-tyrosine powder without mixing treated skin had 50% improvement in contrast to the untreated with gelatin powder. Each capsule thus prepared contained or vehicle control as judged by clinical evaluation. 30 120 mg N-(phosphonomethyl)-L-tyrosine. The above results show that another representative A Subject can take orally one or two capsules per day for N-(phosphonomethyl)-amino acid derivative would be thera systemic administration to alleviate or improve cosmetic con peutically effective for topical treatment of disturbed kerati ditions, or medical disorders, symptoms or syndromes asso nization and inflammatory conditions including erythema, ciated with the nervous, vascular, musculoskeletal or cutane eczema, dermatitis, dermatoses, itch, psoriasis, acne and 35 ous system, or others. OSaCCa. EXAMPLE 38 EXAMPLE 32 N-(Phosphonomethyl)-L-serine crystals were converted to N-(phosphonomethyl)-y-aminobutanoic acid (10 g) was fine powder by grinding with mortar and pestle. Lilly(R) gela dissolved in water (20 ml) and propylene glycol (10 ml), and 40 tin capsules size No. 1, were filled to the top with the solution thus obtained was mixed with hydrophilic oint N-(phosphonomethyl)-L-serine powder without mixing with ment (oil-in-water emulsion, 60 g). The white cream thus gelatin powder. Each capsule thus prepared contained 130 mg formulated had pH 1.9 and contained 10% N-(phosphonom N-(phosphonomethyl)-L-serine. ethyl)-y-aminobutanoic acid. A Subject can take orally one or two capsules per day for 45 systemic administration to alleviate or improve cosmetic con EXAMPLE 33 ditions, or medical disorders, symptoms or syndromes asso ciated with the nervous, vascular, musculoskeletal or cutane N-(phosphonomethyl)-L-glutathione (5 g) was dissolved ous system, or others. in (95 ml) of a warm solution prepared from water (40 parts by Volume), ethanol (40 parts by Volume) and propylene glycol 50 EXAMPLE 39 (20 parts by volume). The composition thus prepared had pH 2.3 and contained 5% N-(phosphonomethyl)-L-glutathione N-(Phosphonomethyl)-L-proline crystals were converted in Solution. to fine powder by grinding with mortar and pestle. Lilly(R) gelatin capsules size No. 1, were filled to the top with EXAMPLE 34 55 N-(phosphonomethyl)-L-proline powder without mixing with gelatin powder. Each capsule thus prepared contained N-(phosphonomethyl)-L-cysteine (5 g) was dissolved in 150 mg N-(phosphonomethyl)-L-proline. (95 ml) of a warm solution prepared from water (40 parts by A Subject can take orally one or two capsules per day for Volume), ethanol (40 parts by Volume) and propylene glycol systemic administration to alleviate or improve cosmetic con (20 parts by volume). The composition thus prepared had pH 60 ditions, or medical disorders, symptoms or syndromes asso 2.7 and contained 5% N-(phosphonomethyl)-L-cysteine in ciated with the nervous, vascular, musculoskeletal or cutane Solution. ous system, or others. EXAMPLE 35 EXAMPLE 40 65 N-(phosphonomethyl)-guanidinoacetic acid N-(phospho N-(Phosphonomethyl)-creatinine (5g) was dissolved in 95 nomethyl)-glycocyamine, 1 g was dissolved in a solution (99 ml of a solution prepared from water (80 parts by volume) and US 7,776,844 B2 31 32 propylene glycol (20 parts by Volume). The liquid composi having 7 to 19 carbon atoms; and the Hattached to any tion thus prepared had pH 4.8 and contained 5% N-(phospho carbon atom can be substituted by I, F, Cl, Br, OH or an nomethyl)-creatinine. This composition would be topically alkoxy group having 1 to 9 carbon atoms; and effective for treatment or prevention of cosmetic conditions wherein the N-(phosphonoalkyl)-amino acid, related com or medical disorders, symptoms or syndromes associated 5 pound or derivative thereof is in a form as a free acid, with nervous, vascular, musculoskeletal or cutaneous system, salt, partial salt, lactone, amide or ester, or in Stereoiso or others. meric or non-stereoisomeric form. 2. The composition of claim 1, wherein the related com EXAMPLE 41 pound or derivative is an N,N-bis(phosphonoalkyl)-amino 10 acid or an N,N'-bis(phosphonoalkyl)-amino acid. N-(Phosphonomethyl)-L-ornithine (8 g) was dissolved in 3. The composition of claim 2, wherein the related com 92 ml of a solution prepared from water (80 parts by volume) pound or derivative is an N,N-bis(phosphonomethyl)-amino and propylene glycol (20 parts by Volume). The liquid com acid or an N,N'-bis(phosphonomethyl)-amino acid. position thus prepared had pH 1.4 and contained 8% 4. The composition of claim 3, wherein the N,N-bis N-(phosphonomethyl)-L-ornithine. This composition would 15 (phosphonomethyl)-amino acid or N,N'-bis(phosphonom be topically effective for treatment or prevention of cosmetic ethyl)-amino acid in a form as a free acid, salt, partial salt, conditions or medical disorders, symptoms or syndromes lactone, amide or ester, or in Stereoisomeric or non-stereoi associated with nervous, vascular, musculoskeletal or cuta Someric form, is selected from the group consisting of N.N- neous system, or others. bis(phosphonomethyl)-alanine; N.N-bis(phosphonomethyl)- arginine; N.N-bis(phosphonomethyl)-aspartic acid; N,N-bis EXAMPLE 42 (phosphonomethyl)-asparagine; N,N-bis (phosphonomethyl)-cysteine; N.N-bis(phosphonomethyl)- N,N-Bis(phosphonomethyl)-glycine (2.5 g) was dissolved glycine; N.N-bis(phosphonomethyl)-glutamic acid; N,N-bis in water (10 ml), and the solution thus obtained was mixed (phosphonomethyl)-glutamine; N.N-bis(phosphonomethyl)- with hydrophilic ointment (oil-in-water emulsion, 87.5 g). 25 histidine; N.N-bis(phosphonomethyl)-isoleucine; N.N-bis The white cream thus formulated had pH 1.3 and contained (phosphonomethyl)-leucine; N.N-bis(phosphonomethyl)- 2.5% N,N-bis(phosphonomethyl)-glycine. lysine; N.N-bis(phosphonomethyl)-methionine; N.N-bis (phosphonomethyl)-phenylalanine; N,N-bis EXAMPLE 43 (phosphonomethyl)-serine; N,N-bis(phosphonomethyl)- 30 threonine; N,N-bis(phosphonomethyl)-tryptophan; N,N-bis N-(phosphonomethyl)-4-guanidinobutanoic acid (5 g) was (phosphonomethyl)-tyrosine; N.N-bis(phosphonomethyl)- dissolved in water (20 ml), and the solution thus obtained was valine; N,N'-bis(phosphonomethyl)-arginine: N,N'-bis mixed with hydrophilic ointment (oil-in-water emulsion, 75 (phosphonomethyl)-histidine; N.N'-bis(phosphonomethyl)- g). The white cream thus formulated had pH 1.8 and con lysine and N,N'-bis(phosphonomethyl)-tryptophan. tained 5% N-(phosphonomethyl)-4-guanidinobutanoic acid. 35 5. The composition of claim 3, wherein the related com It will be appreciated by those skilled in the art that changes pound or compound derived therefrom in a form as a free could be made to the embodiments described above without acid, salt, partial salt, lactone, amide or ester, or in Stereoiso departing from the broad inventive concept thereof. It is meric or non-stereoisomeric form, is selected from the group understood, therefore, that this invention is not limited to the consisting of N,N-bis(phosphonomethyl)-f-alanine; N.N-bis particular embodiments disclosed, but it is intended to cover 40 (phosphonomethyl)-y-aminobutanoic acid; N,N-bis modifications within the spirit and scope of the present inven (phosphonomethyl)-3-aminoisobutanoic acid: N,N-bis tion as defined by the appended claims. (phosphonomethyl)-anserine; N.N-bis(phosphonomethyl)- We claim: aminolevulinic acid; N,N-bis(phosphonomethyl)-carnosine; 1. A composition comprising an N-(phosphonoalkyl)- N,N-bis(phosphonomethyl)-canaline; N,N-bis(phospho amino acid, a related compound or a derivative thereof in a 45 nomethyl)-canavanine; N.N-bis(phosphonomethyl)-citrul form as a free acid, salt, partial salt, lactone, amide orester, or line; N,N-bis(phosphonomethyl)-creatine; N,N-bis in Stereoisomeric or non-stereoisomeric form, and a cosmeti (phosphonomethyl)-creatinine; N.N-bis(phosphonomethyl)- cally or pharmaceutically acceptable vehicle for topical or cysteine sulfinic acid: N,N-bis(phosphonomethyl)-cystine: systemic administration to a mammalian Subject for treat N,N-bis(phosphonomethyl)-cycloserine; N.N-bis(phospho ment of a cosmetic condition or dermatological disorder; 50 nomethyl)-dopa N,N-bis(phosphonomethyl)-3,4-dihydrox wherein the N-(phosphonoalkyl)-amino acid, related com yphenylalanine; N.N-bis(phosphonomethyl)-dopamine(hy pound or derivative thereof is N-(phosphonoalkyl)-pro droxytyramine); N,N-bis(phosphonomethyl)-ethionine: line or has the following formula: N,N-bis(phosphonomethyl)-glutathione; N.N-bis(phospho nomethyl)-guanidinoacetic acid; N,N-bis(phosphonom 55 ethyl)-3-guanidinopropanoic acid; N,N-bis(phosphonom wherein R is H, and alkyl group having 1 to 19 carbon ethyl)-4-guanidinobutanoic acid; N,N-bis atoms, an aryl group having 6 to 19 carbon atoms or an (phosphonomethyl)-homocamosine; N,N-bis aralkyl group having 7 to 19 carbon atoms; and R can (phosphonomethyl)-homocysteine; N,N-bis also carry —OH, -SH, —SCH. —NH, —NRR, (phosphonomethyl)-homoserine; N,N-bis - COR - NHCONH, -NHC(=NR)NH, imida 60 (phosphonomethyl)-4-hydroxyphenylglycine; N,N-bis Zole, pyrrolidine or other heterocyclic group; m is an (phosphonomethyl)-hydroxyglutamic acid; N,N-bis integer from 0 to 5; R is a phosphonoalkyl group having (phosphonomethyl)-hydroxylysine; N,N-bis a formula (HO),PO(CH.) : R is H or a phospho (phosphonomethyl)-hydroxyproline; N,N-bis noalkyl group having a formula (HO)PO(CH), ; n is (phosphonomethyl)-hypusine; N.N-bis(phosphonomethyl)- an integer from 1 to 9; R is NH or —ORs. Rs is H. 65 homoarginine; N.N-bis(phosphonomethyl)-homocitrulline; and alkyl group having 1 to 19 carbon atoms, an aryl N,N-bis(phosphonomethyl)-homocystine; N.Nbis(phospho group having 6 to 19 carbon atoms or an aralkyl group nomethyl)-homophenylalanine; N,N-bis(phosphonom US 7,776,844 B2 33 34 ethyl)-homotryptophan; N,N-bis(phosphonomethyl)-hy ethionine, N-(phosphonomethyl)-glutathione, droxylysine; N.N-bis(phosphonomethyl)-hydroxyarginine; N-(phosphonomethyl)-guanidinoacetic acid, N-(phospho N,N-bis(phosphonomethyl)-hydroxyhomoarginine; N.N-bis nomethyl)-3-guanidinopropanoic acid, N-(phosphonom (phosphonomethyl)-hydroxycitrulline; N.N-bis(phospho ethyl)-4-guanidinobutanoic acid, N-(phosphonomethyl)-ho nomethyl)-hydroxyomithine; N.N-bis(phosphonomethyl)- mocarnosine, N-(phosphonomethyl)-homocysteine, hydroxyvaline; N.N-bis(phosphonomethyl)-indospicine; N-(phosphonomethyl)-homoserine, N-(phosphonomethyl)- N,N-bis(phosphonomethyl)-methoxinine: N,N-bis 4-hydroxyphenylglycine, N-(phosphonomethyl)-hydroxy (phosphonomethyl)-methylarginine; N.N-bis(phosphonom glutamic acid, N-(phosphonomethyl)-hydroxylysine, ethyl)-methylhistidine; N.N-bis(phosphonomethyl)-meth N-(phosphonomethyl)-hydroxyproline, N-(phosphonom yllysine; N.N-bis(phosphonomethyl)-methylornithine; N.N- 10 ethyl)-hypusine, N-(phosphonomethyl)-homoarginine, bis(phosphonomethyl)-methylserine; N,N-bis N-(phosphonomethyl)-homocitrulline, N-(phosphonom (phosphonomethyl)-norvaline; N.N-bis(phosphonomethyl)- ethyl)-homocystine, N-(phosphonomethyl)-homophenylala ornithine; N.N-bis(phosphonomethyl)-oxalysine; N.N-bis nine, N-(phosphonomethyl)-homotryptophan, N-(phospho (phosphonomethyl)-penicillamine(N-phosphonomethyl nomethyl)-hydroxylysine, N-(phosphonomethyl)- dimethylcysteine); N,N-bis(phosphonomethyl)- 15 hydroxyarginine, N(phosphonomethyl)- phenylglycine; N.N-bis(phosphonomethyl)-3-phenylserine; hydroxyhomoarginine, N-(phosphonomethyl)- N,N-bis(phosphonomethyl)-sarcosine (N-phosphonom hydroxycitrulline, N-(phosphonomethyl)-hydroxyomithine, ethyl-N-methyl-glycine); N,N-bis(phosphonomethyl)-sero N-(phosphonomethyl)-hydroxyvaline, N-(phosphonom tonin (N-phosphonomethyl-hydroxytryptamine); N,N-bis ethyl)-indospicine, N-(phosphonomethyl)-methoxinine, (phosphonomethyl)-taurine; N.N-bis(phosphonomethyl)- N-(phosphonomethyl)-methylarginine, N-(phosphonom tryptamine; N.N-bis(phosphonomethyl)-tyramine and N,N'- ethyl)-methylhistidine, N-(phosphonomethyl)-methyllysine, bis(phosphonomethyl)-ornithine. N-(phosphonomethyl)-methylornithine, N-(phosphonom 6. The composition of claim 1, wherein the phospho ethyl)-methylserine, N-(phosphonomethyl)-norvaline, noalkyl of the N-(phosphonoalkyl)-amino acid compound, N-(phosphonomethyl)-ornithine, N-(phosphonomethyl)-ox related compound or compound derived therefrom is selected 25 alysine, N-(phosphonomethyl)-penicillamine(N-phospho from the group consisting of phosphonomethyl, phosphono nomethyl-dimethylcysteine), N-(phosphonomethyl)-phe ethyl, phosphonopropyl, phosphonoisopropyl, phospho nylglycine, N-(phosphonomethyl)-3-phenylserine, nobutyl, phosphonoisobutyl, phosphonopentyl, phospho N-(phosphonomethyl)-sarcosine (N-phosphonomethyl-N- noisopentyl, phosphonooctyl and phosphonoisooctyl. methyl-glycine), N-(phosphonomethyl)-serotonin 7. The composition of claim 1, wherein the compound is an 30 (N-phosphonomethyl-hydroxytryptamine), N-(phospho N-(phosphonoalkyl)-amino acid. nomethyl)-taurine, N-(phosphonomethyl)-tryptamine and 8. The composition of claim 1, wherein the compound is an N-(phosphonomethyl)-tyramine. N-(phosphonomethyl)-amino acid. 11. The composition of claim 1, wherein the N-(phospho 9. The composition of claim 8, wherein the N-(phospho noalkyl)-amino acid compound, related compound or com nomethyl)-amino acidina form as a free acid, salt, partial salt, 35 pound derived therefrom in a form as a free acid, salt, partial lactone, amide or ester, or in a stereoisomeric or non-stereoi salt, lactone, amide or ester, or in Stereoisomeric or non Someric form, is selected from the group consisting of Stereoisomeric form, is selected from the group consisting of N-(phosphonomethyl)-alanine, N-(phosphonomethyl)-argi N-(phosphonomethyl)-asparagine, N-(phosphonomethyl)- nine, N-(phosphonomethyl)-asparagine, N-(phosphonom asparaginamide, N-(phosphonomethyl)-aminobutanoic acid, ethyl)-aspartic acid, N-(phosphonomethyl)-cysteine, 40 N-(phosphonomethyl)-arginine, N-(phosphonomethyl)- N-(phosphonomethyl)-glutamic acid, N-(phosphonom argininamide, N-(phosphonomethyl)-arginine ethyl ester, ethyl)-glutamine, N-(phosphonomethyl)-glycine, N-(phosphonomethyl)-creatine, N-(phosphonomethyl)-crea N-(phosphonomethyl)-histidine, N-(phosphonomethyl)-iso tinine, N-(phosphonomethyl)-cysteine, N-(phosphonom leucine, N-(phosphonomethyl)-leucine, N-(phosphonom ethyl)-glutamic acid, N-(phosphonomethyl)-glutamic acid ethyl)-lysine, N-(phosphonomethyl)-methionine, 45 diethyl ester, N-(phosphonomethyl)-glutamine, N-(phospho N-(phosphonomethyl)-phenylalanine, N-(phosphonom nomethyl)-glutaminamide, N-(phosphonomethyl)- ethyl)-proline, N-(phosphonomethyl)-serine, N-(phospho glutamine ethyl ester, N-(phosphonomethyl)-glutathione, nomethyl)-threonine, N-(phosphonomethyl)-tryptophan, N-(phosphonomethyl)-glycine, N-(phosphonomethyl)-gly N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)- cinamide, N-(phosphonomethyl)-glycine ethyl ester, Valine. 50 N-(phosphonomethyl)-glycine propyl ester, N-(phospho 10. The composition of claim 1, wherein the N-(phospho nomethyl)-glycine isopropyl ester, N-(phosphonomethyl)-4- noalkyl)-amino acid compound, related compound or com hydroxyphenylglycine, N-(phosphonomethyl)-lysine, pound derived therefrom in a form as a free acid, salt, partial N-(phosphonomethyl)-lysinamide, N-(phosphonomethyl)- salt, lactone, amide or ester, or in Stereoisomeric or non lysine ethyl ester, N-(phosphonomethyl)-ornithine, Stereoisomeric form, is selected from the group consisting of 55 N-(phosphonomethyl)-proline, N-(phosphonomethyl)-proli N-(phosphonomethyl)-alanine, N-(phosphonomethyl)-ami namide, N-(phosphonomethyl)-proline ethyl ester, nobutanoic acid, N-(phosphonomethyl)-aminoisobutanoic N-(phosphonomethyl)-proline propyl ester, N-(phospho acid, N-(phosphonomethyl)-anserine, N-(phosphonom nomethyl)-proline isopropyl ester, N-(phosphonomethyl)- ethyl)-aminolevulinic acid, N-(phosphonomethyl)-carnos serine, N-(phosphonomethyl)-tyrosine and N-(phosphonom ine, N-(phosphonomethyl)-canaline, N-(phosphonomethyl)- 60 ethyl)-tyramine. canavanine, N-(phosphonomethyl)-citrulline, 12. The composition of claim 1, wherein the composition N-(phosphonomethyl)-creatine, N-(phosphonomethyl)-crea further comprises a cosmetic or pharmaceutical agent. tinine, N-(phosphonomethyl)-cysteine Sulfinic acid, 13. The composition of claim 12, wherein the cosmetic or N-(phosphonomethyl)-cystine, N-(phosphonomethyl)-cy pharmaceutical agent is selected from the group consisting of closerine, N-(phosphonomethyl)-dopa N-(phosphonom 65 hydroxyacids, ketoacids and related compounds; phenyl ethyl)-3,4-dihydroxyphenylalanine, N-(phosphonomethyl)- alpha acyloxyalkanoic acids and derivatives; N-acyl-al dopamine(hydroxytyramine), N-(phosphonomethyl)- dosamines, N-acylamino acids and related N-acyl com US 7,776,844 B2 35 36 pounds; local analgesics and anesthetics; anti-acne agents; chlorpromazine, chlorpropamide, ciclopiroX, cilostaZol. anti-bacterial agents; anti-yeast agents; anti-fungal agents; cimetidine, cinacalcet, ciprofloxacin, citalopram, citric acid, anti-viral agents; anti-infective agents; anti-dandruff agents; cladribine, clarithromycin, clemastine, clindamycin, clio anti-dermatitis agents; anti-eczema agents; anti-histamine quinol, clobetasol propionate, clocortolone pivalate, clomi agents; anti-pruritic agents; anti-emetics; anti-motion sick phene, clonidine, clopidogrel, clotrimazole, clozapine, coal ness agents; anti-inflammatory agents; anti-hyperkeratotic tar, coal tar extracts (LCD), codeine, cromolyn, crotamiton, agents; antiperspirants; anti-psoriatic agents; anti-rosacea cyclizine, cyclobenzaprine, cycloserine, cytarabine, dacarba agents; anti-seborrheic agents; hair conditioners and hair Zine, dalfopristin, dapsone, daptomycin, daunorubicin, def treatment agents; anti-aging and anti-wrinkle agents; anti eroxamine, dehydroepiandrosterone, delavirdine, anxiety agents; anti-convulsant agents; anti-depressant 10 desipramine, desloratadine, desmopressin, desoximetaSone, agents; Sunblock and Sunscreen agents; skin lightening dexamethasone, dexmedetomidine, dexmethylphenidate, agents; depigmenting agents; astringents; cleansing agents: dexraZoxane, dextroamphetamine, diazepam, diclofenac, corn, callus or wart removing agents; skin plumping agents; dicyclomine, didanosine, dihydrocodeine, dihydromorphine, skin Volumizing agents; skin firming agents; matrix metallo diltiazem, 6,8-dimercaptooctanoic acid (dihydrolipoic acid), proteinase (MMP) inhibitors; topical cardiovascular agents: 15 diphenhydramine, diphenoxylate, dipyridamole, disopyra wound-healing agents; gum disease or oral care agents; mide, dobutamine, dolfetilide, dolasetron, donepezil, dopa amino acids; peptides; dipeptides; tripeptides; glutathione esters, dopamide, dopamine, dorzolamide, doxepin, doxoru and its derivatives; oligopeptides; polypeptides; carbohy bicin, doxycycline, doxylamine, doxepin, dulloxetine, dyclo drates; aminocarbohydrates; vitamins; corticosteroids; tan nine, econazole, efalizumab, eflomithine, eletriptan, emitric ning agents; hormones and retinoids. itabine, enalapril, ephedrine, epinephrine, epinine, 14. The composition of claim 12, wherein the cosmetic or epirubicin, eptifibatide, ergotamine, erythromycin, escitalo pharmaceutical agent as stated or as free base, free acid, ester, pram, esmolol, esomeprazole, estazolam, estradiol, etaner amide, lactone or salt form is selected from the group con cept, ethacrynic acid, ethinyl estradiol, etidocaine, etomidate, sisting of abacavir, abciximab, acamprosate, acarbose, ace famciclovir, famotidine, felodipine, fentanyl, ferulic acid, butolol, acetaminophen, acetaminoSalol, acetazolamide, ace 25 fexofenadine, flecamide, fluconazole, flucytosine, fluocino tic acid, acetohydroxamic acid, N-acetylcysteine and its lone acetonide, fluocinonide, 5-fluorouracil, fluoxetine, esters, N-acetylglutathione and its esters, acitretin, aclometa fluphenazine, flurazepam, fluticaSone propionate, fluvoxam Sone dipropionate, acrivastine, acthrel, actidose, actigall, acy ine, formoterol, furosemide, galactarolactone, galactonic clovir, adalimumab, adapalene, adefovir dipivoxil, adenos acid, galactonolactone, galantamine, gatifloxacin, gefitinib, ine, agallsidase, albendazole, albumin, albuterol, aldesleukin, 30 gemcitabine, gemifloxacin, glucarolactone, gluconic acid, alefacept, alemtuzumab, alendronate, alfuzosin, alitretinoin, gluconolactone, glucuronic acid, glucuronolactone, glycolic allantoin, allium, allopurinol, alloxanthine, almotriptan, alos acid, griseofulvin, guaifenesin, guanethidine, N-guanylhista etron, alpha tocopheral, alpha-proteinase, alprazolam, alpre mine, haloperidol, haloprogin, hexylresorcinol, homatropine, nolol, alprostadil, alteplase, altretamine, aluminum acetate, homosalate, hydralazine, hydrochlorothiazide, hydrocorti aluminum chloride, aluminum chlorohydroxide, aluminum 35 Sone, hydrocortisone 21-acetate, hydrocortisone 17-butyrate, hydroxide, amantadine, amifostine, amiloride, aminacrine, hydrocortisone 17-Valerate, hydrogen peroxide, hydromor amino acid, aminobenzoate, p-aminobenzoic acid, aminoca phone, hydroquinone, hydroquinone monoether, hydrox proic acid, aminohippurate, aminolevulinic acid, aminosali yZine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol. cylic acid, amiodarone, amitriptyline, amlodipine, idarubicin, imatinib, imipramine, imiquimod, indinavir, amocarzine, amodiaquin, amorolfine, amoxapine, amoxicil 40 indomethacin, infliximab, irbesartan, irinotecan, isoetharine, lin, amphetamine, amphotericin, ampicillin, amprenavir, isoproterenol, itraconazole, kanamycin, ketamine, ket anagrelide, anakinra, anastroZole, anisindione, anthralin, anserin, ketoconazole, ketoprofen, ketotifen, kojic acid, labe antihemophilic, antithrombin, anti-thymocyte, antivenin, talol, lactic acid, lactobionic acid, lamivudine, lamotrigine, apomorphine, aprepitant, aprotinin, arbutin, argatroban, arip lansoprazole, letrozole, leuprolide, levalbuterol, levofloxa iprazole, arnica, ascorbic acid and its esters, ascorbyl palmi 45 cin, lidocaine, lineZolid, lobeline, loratadine, loperamide, tate, aspirin, atazanavir, atenolol, atomoxetine, atorvastatin, losartan, loxapine, lysergic diethylamide, mafenide, malic atovaquone, atropine, azathioprine, azelaic acid, azelastine, acid, maltobionic acid, mandelic acid, maprotiline, mebenda azithromycin, baclofen, bacitracin, balsalazide, balsam, Zole, mecamylamine, meclizine, meclocycline, memantine, basiliximab, beclomethasone dipropionate, bemegride, menthol, meperidine, mepivacaine, meduinol, mercaptopu benazepril, bendroflumethiazide, benzocaine, benzonatate, 50 rine, mescaline, metanephrine, metaproterenol, metaraminol, benzophenone, benzoyl peroxide, benztropine, bepridil, beta metformin, methadone, methamphetamine, methotrexate, carotene, betamethasone dipropionate, betamethasone Valer methoxamine, methyldopa esters, methyldopamide, 3.4-me ate, betaxolol, bethanechol, bevacizumab, bexarotene, thylenedioxymethamphetamine, methylactic acid, methyl bicalutamide, bimatoprost, bioflavonoids, biotin, biperiden, nicotinate, methylphenidate, methyl salicylate, metiamide, bisacodyl, bisoprolol, bivalirudin, bortezomib, bosentan, 55 metolaZone, metoprolol, metronidazole, mexiletine, micona botulinum, brimonidine, brinzolamide, bromocriptine, bro Zole, midazolam, midodrine, miglustat, minocycline, mpheniramine, budesonide, bumetanide, bupivacaine, minoxidil, mirtazapine, mitoxantrone, moexiprilat, molin buprenorphine, bupropion, burimamide, buspirone, buSulfan, done, monobenzone, morphine, moxifloxacin, moxonidine, butabarbital, butalbital, butenafine, butoconazole, butorpha mupirocin, nadolol, naftifine, nalbuphine, nalmefene, nalox nol, butylaminobenzoate, cabergoline, caffeic acid, caffeine, 60 one, naproxen, nefazodone, nelfinavir, neomycin, nevirapine, calcipotriene, calcitonin-Salmon, calcitriol, calfactant, nicardipine, nicotine, nifedipine, nimodipine, nisoldipine, camelia sinensis, camphor, candesartan cilexetil, capecitab nitrofurantoin, nizatidine, norepinephrine, nystatin, octo ine, capreomycin, capsaicin, captopril, carbamazepine, car pamine, octreotide, octyl methoxycinnamate, octyl salicy bamide peroxide, carbidopa, carbinoxamine, cefditoren piv late, ofloxacin, olanzapine, olmesartan medoxomil, olopata oxil, cefepime, cefpodoxime proxetil, celecoxib, cetirizine, 65 dine, omeprazole, ondansetron, oxiconazole, oxotremorine, cevimeline, chitosan, chlordiazepoxide, chlorhexidine, chlo oxybenzone, oxybutynin, oxycodone, oxymetazoline, padi roquine, chlorothiazide, chloroxylenol, chlorpheniramine, mate O, palonosetron, pantothenic acid, pantoyl lactone, par US 7,776,844 B2 37 38 oxetine, pemoline, penciclovir, penicillamine, penicillins, conazole, warfarin, wood tar, Xanthine, Zafirlukast, Zaleplon, pentazocine, pentobarbital, pentostatin, pentoxifylline, per Zinc pyrithione, Ziprasidone, Zolmitriptan and Zolpidem. golide, perindopril, permethrin, phencyclidine, phenelzine, 15. The composition of claim 1, pheniramine, phenmetrazine, phenobarbital, phenol, phe wherein the treatment of a cosmetic condition ordermato noxybenzamine, phentolamine, phenylephrine, phenylpro logical disorder is treatment of a cosmetic condition of panolamine, phenyloin, physostigmine, pilocarpine, pime dermatological disorder selected from the group consist crolimus, pimozide, pindolol, pioglitaZone, pipamazine, ing of disturbed keratinization; changes associated with piperonylbutoxide, pirenzepine, podofilox, povidone iodine, intrinsic and extrinsic aging; acne, rosacea; age spots; pramipexole, pramoxine, prazosin, prednisone, prenalterol, blemished skin; blotches; cellulite; dermatoses; derma prilocalne, procainamide, procaine, procarbazine, pro 10 titis; skin, nail and hair infections; dandruff, dryness or mazine, promethazine, promethazine propionate, pro looseness of skin, nail and hair, Xerosis: eczema: elas pafenone, propoxyphene, propranolol, propylthiouracil, pro tosis; herpes; hyperkeratosis; hyperpigmented skin; ich triptyline, pseudoephedrine, pyrethrin, pyrilamine, tyosis; keratoses; lentigines; melasmas; mottled skin; pyrimethamine, quetiapine, quinapril, quinethaZone, quini pseudofolliculitis barbae; photoaging and photodam dine, quinupristin, rabeprazole, reserpine, resorcinol, retinal, 15 age; pruritus; psoriasis; skin lines; stretch marks; thin 13-cis retinoic acid, retinoic acid, retinol, retinyl acetate, ning of skin, nail plate and hair, warts; wrinkles; break retinyl palmitate, ribavirin, ribonic acid, ribonolactone, down, defective synthesis or repair of dermal rifampin, rifapentine, rifaximin, riluzole, rimantadine, components; abnormal or diminished synthesis of col risedronic acid, risperidone, ritodrine, rivastigmine, rizatrip lagen, glycosaminoglycans, proteoglycans or elastin, tan, ropinirole, ropivacaine, salicylamide, Salicylic acid, sal diminished levels of collagen, glycosaminoglycans, meterol, Scopolamine, selegiline, selenium sulfide, serotonin, proteoglycans or elastin in the dermis; uneven skintone; Sertaconazole, sertindole, Sertraline, shale tar, Sibutramine, uneven and rough Surface of skin, nail and hair, loss or sildenafil. Sotalol, Streptomycin, Strychnine, Sulconazole, Sul reduction of skin, nail and hair resiliency, elasticity and facetamide, Sulfabenz, Sulfabenzamide, SulfabromomethaZ recoilability: laxity; lack of skin, nail and hair lubricants ine, Sulfacetamide (sodium sulfacetamide), Sulfachlorpy 25 and luster, fragility and splitting of nail and hair, yellow ridazine, Sulfacytine, Sulfadiazine, Sulfadimethoxine, ing skin; reactive, irritating or telangiectatic skin; dull Sulfadoxine, Sulfaguanole, Sulfalene, Sulfamethizole, Sul and older-looking skin, nail and hair; or famethoxazole, Sulfanilamide, Sulfapyrazine, Sulfapyridine, wherein the treatment of a cosmetic condition ordermato Sulfasalazine, Sulfasomizole, Sulfathiazole, Sulfisoxazole, logical disorder is for general care of skin, nail and hair; 30 to improve skin texture and pores, flakiness and redness; Sulfur, tacrolimus, tadalafil, tamsulosin, tartaric acid, tazaro to make skin soft, Smooth, fresh, balanced, visibly clear, tene, tegaserod, tellithromycin, telmisartan, temozolomide, even-toned and brighter; to increase skin fullness and tenofovir disoproxil, terazosin, terbinafine, terbutaline, ter plumpness; for skin bleach and lightning; or wound conazole, terfenadine, tetracaine, tetracycline, tetrahydroZo healing. line, thalidomide, theobromine, theophylline, thiabendazole, 35 16. The composition of claim 1, wherein the N-(phospho thioctic acid (lipoic acid), thioridazine, thiothixene, thymol. noalkyl)-amino acid is N-(phosphonomethyl)-glycine and tiagabine, timolol, timidazole, tioconazole, tirofiban, tizani dine, tobramycin, tocamide, tolazoline, tolbutamide, tolnaf the composition is used for systemic administration to the tate, tolterodine, tramadol, tranylcypromine, traZodone, tri mammalian Subject for treatment of a cosmetic condition or ameinolone acetonide, triamcinolone diacetate, dermatological disorder. triamcinolone hexacetonide, triamterene, triazolam, tri 40 17. The composition of claim 16, wherein the cosmetic closan, triflupromazine, trimethoprim, trimipramine, tripe condition or dermatological disorder is selected from the lennamine, triprolidine, tromethamine, tropic acid, tyramine, group consisting of disturbed keratinization; acne; hyperk undecylenic acid, urea, urocanic acid, ursodiol, Valacyclovir, eratosis and ichthyosis. Vardenafil. Venlafaxine, Verapamil, vitamin E acetate, Vori k k k k k